1: Clin Genet 2002 Jan;61(1):54-61
Partial Xp duplication in a girl with dysmorphic features: the change in
replication pattern of late- replicating dupX chromosome.
Kokalj Vokac N, Seme Ciglenecki P, Erjavec A, Zagradisnik B, Zagorac A.
Maribor Teaching Hospital, Laboratory of Medical Genetics, Maribor, Slovenia;
Primary Health Center, Maribor, Slovenia, Tel.: + 386 2321 29 46; Fax: + 386
2331 23 93e- mail: nadja.kokalj- vokac@sb- mb.si
In this paper we present the case of a girl at the age of 32 months with
dysmorphic features, including general muscular hypotonia, developmental delay
and mental retardation. The cytogenetic analysis revealed de novo partial
duplication of Xp: 46,X,dup(X)(p11.23--p22.33: :p11.23-- p22.33). To
characterize the duplication, X painting, Kallman (KAL), yeast artificial
chromosomes (YACs) and bacterial artificial chromosomes (BACs) covering
Xp11.23-- >Xp22.33 region were used. Selective inactivation of the abnormal X
chromosome using HpaII digestion of the AR gene was evident. After BrdU
incorporation the abnormal X was late- replicating in all lymphocytes examined.
There was one peculiar exception observed: the break- point region was
consistently early replicating. The replicating pattern of this region
corresponded to the active X chromosome. Methylation pattern of late replicating
X chromosome was studied also using antibodies against 5- methylcytosine. The
pattern corresponded to the normally inactive X chromosome, with the exception
of the previously observed break- point region which revealed an early
replicating pattern with strong fluorescent signal, similar to the pattern of
the active X chromosome. The observed phenomenon could lead to the abnormal
phenotype of the patient, with some normally inactive genes of the break- point
region escaping the inactivation process. The abnormal clinical findings could
also be due to tissue- dependent differences in the inactivation pattern.
PMID: 11903357 [PubMed - in process]
2: J Neurol 2001 Oct;248(10):856- 60
Clinical features and skewed X- chromosome inactivation in female carriers of
X- linked recessive spinal and bulbar muscular atrophy.
Ishihara H, Kanda F, Nishio H, Sumino K, Chihara K.
Department of Medicine, Kobe University School of Medicine, Japan.
In X- linked recessive disorders, a few female gene carriers become symptomatic.
Recent evidence implicates skewed X- chromosome inactivation in such female
carriers. We studied the clinical features of eight female gene carriers of
X- linked recessive spinal and bulbar muscular atrophy (SBMA), and evaluated the
relationship between phenotype and genotype from the viewpoint of X- chromosome
inactivation. Seven of eight cases were symptomatic, showing mild muscle
weakness, frequent muscle cramps, slight elevation of the serum creatinine
kinase level, or neurogenic changes on the electromyogram. Only one carrier was
asymptomatic clinically. For the estimation of X- chromosome inactivation, the
methylation status of the androgen receptor (AR) gene was determined by
polymerase chain reaction- based assay. Highly skewed inactivation of the
affected AR gene was found in the asymptomatic carrier, while symptomatic
carriers had a random or lower inactivation pattern of the affected AR gene.
These findings suggest that most female carriers of SBMA show some clinical
abnormalities, and highly skewed inactivation of the affected X- chromosome seems
to closely relate with escape of the manifestation in female carriers of SBMA.
PMID: 11697521 [PubMed - indexed for MEDLINE]
3: Neuromuscul Disord 2001 Jul;11(5):494- 8
Pseudo- metabolic presentation in a Duchenne muscular dystrophy symptomatic
carrier with 'de novo' duplication of dystrophin gene.
Romero NB, De Lonlay P, Llense S, Leturcq F, Touati G, Urtizberea JA, Saudubray
JM, Munnich A, Kaplan JC, Recan D.
INSERM U523 and Institut de Myologie, Hopital de la Salpetriere; 47 Boulevard de
l'Hopital, 75013, Paris, France. nb.romero@myologie.chups.jussieu.fr
We report a 6- year- old female patient presenting with a sudden and severe single
episode of rhabdomyolysis in which screening for a metabolic disorder was
negative. Four months after the episode a muscle biopsy was performed and showed
a mild pattern of necrosis/regeneration. Upon immunofluorescence, a mosaic
pattern of dystrophin deficiency was found, and in the dystrophin deficient
muscle fibres, the four proteins of the sarcoglycan complex were also lacking.
Genetic analysis showed a duplication of exons 3 to 17 on one X- chromosome of
the proband, but not on the mother's X- chromosome. A clearly skewed
X- inactivation (85% of the defective X being active) was found and is consistent
with the patient being symptomatic. To our knowledge, a spontaneous
rhabdomyolysis in a female Duchenne muscular dystrophy carrier has never been
reported.
PMID: 11404124 [PubMed - indexed for MEDLINE]
4: Mol Endocrinol 1999 Dec;13(12):2065- 75
Erratum in:
Mol Endocrinol 2000 Apr;14(4):544
A C619Y mutation in the human androgen receptor causes inactivation and
mislocalization of the receptor with concomitant sequestration of SRC- 1 (steroid
receptor coactivator 1)
Nazareth LV, Stenoien DL, Bingman WE 3rd, James AJ, Wu C, Zhang Y, Edwards DP,
Mancini M, Marcelli M, Lamb DJ, Weigel NL.
Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, Texas 77030, USA.
Androgen ablation therapy is a primary treatment for advanced prostate cancer,
but tumors become refractive to therapy. Consequently, the role of the androgen
receptors (ARs) and of mutations in the AR in prostate cancer has been a subject
of much concern. In the course of analyzing tumors for mutations, we identified
a somatic mutation that substitutes tyrosine for a cysteine at amino acid 619
(C619Y), which is near the cysteines that coordinate zinc in the DNA binding
domain in the AR. The mutation was re- created in a wild- type expression vector
and functional analyses carried out using transfection assays with
androgen- responsive reporters. The mutant is transcriptionally inactive and
unable to bind DNA. In response to ligand treatment, AR619Y localizes abnormally
in numerous, well circumscribed predominantly nuclear aggregates in the nucleus
and cytoplasm. Interestingly, these aggregates also contain the bulk of the
coexpressed steroid receptor coactivator SRC- 1, suggesting, in analogy to AR in
spinal bulbar muscular atrophy, that this mutant may alter cellular physiology
through sequestration of critical proteins. Although many inactivating mutations
have been identified in androgen insensitivity syndrome patients, to our
knowledge, this is the first characterization of an inactivating mutation
identified in human prostate cancer.
PMID: 10598582 [PubMed - indexed for MEDLINE]
5: Am J Med Genet 1999 Nov 5;87(1):86- 7
Screening of the C43G mutation in the promoter region of the XIST gene in
females with highly skewed X- chromosome inactivation.
Pereira LV, Zatz M.
Publication Types:
Letter
PMID: 10528256 [PubMed - indexed for MEDLINE]
6: Acta Neurol Scand 1999 Oct;100(4):249- 53
Random X chromosome methylation patterns in the carriers with clinical
phenotypic expressions of X- linked recessive bulbospinal neuronopathy.
Chen RS, Huang CC, Chu NS, Cheng CC, Wei YH.
Department of Neurology, Chang Gung Memorial Hospital, Taipei, Taiwan.
OBJECTIVES: We report the unusual phenotypic expression in 2 female carriers of
a family with X- linked recessive bulbospinal neuronopathy (X- BSN). We analyze
the methylation pattern of the androgen receptor (AR) gene to inspect the
possibility of non- random X chromosome inactivation to be the underlying
mechanism. MATERIAL AND METHODS: Twenty- three members in 3 generations of a
Taiwanese family were examined and studied for genomic DNA analysis. We analyzed
the sequence of the first exon of the AR gene to identify the numbers of CAG
repeats, and to determine the methylation pattern by using the restriction
enzymes HpaII and HhaI. RESULTS: There were 3 probands and 5 carriers and 2 of
the carriers manifested clinical symptoms. Sequence analysis revealed that the
numbers of trinucleotide repeats ranged from 42 to 45 in one allele of the
X- chromosome in the 5 female carriers. The restriction pattern of the HpaII and
HhaI recognizable sites of the X- chromosome indicated a random methylation.
CONCLUSION: Our data suggest that molecular genetic studies are important in
confirming the diagnosis of X- BSN and early detection of female carriers, and
the random or non- random methylation pattern of the X- chromosome is not a
determining factor for partial expression of the abnormal AR gene in some
carriers.
PMID: 10510685 [PubMed - indexed for MEDLINE]
7: Am J Med Genet 1999 Aug 27;85(5):476- 8
Prenatal evaluation of a de novo X;9 translocation.
Feldman B, Kramer RL, Ebrahim SA, Wolff DJ, Evans MI.
Division of Reproductive Genetics, Department of Obstetrics and Gynecology,
Wayne State University, Detroit, Michigan 48201, USA.
A case of X- autosome translocation was diagnosed prenatally [46,X, t(X;9)(p21.3
approximately 22.1;q22]. We describe the use of fluorescence in situ
hybridization (FISH) to estimate the integrity of the Duchenne muscular
dystrophy (DMD) gene. X- inactivation studies were used as well to assess the
probability of phenotypic abnormalities associated with functional partial
disomy X and monosomy 9. Copyright 1999 Wiley- Liss, Inc.
PMID: 10405445 [PubMed - indexed for MEDLINE]
8: Acta Neuropathol (Berl) 1999 Jun;97(6):657- 60
Variable histological expression of dystrophinopathy in two females.
Doriguzzi C, Palmucci L, Mongini T, Chiado- Piat L, Saggiorato C, Ugo I, Hoffman
EP.
Centro per le Malattie Neuromuscolari Paolo Peirolo, Torino, Italy.
palmucci@medfarm.unito.it
We report two carriers of Xp21 muscular dystrophy with unusual clinical
manifestations and striking variability of dystrophin deficiency within the same
muscle biopsy. The first patient was a 60- year- old nun with recent onset of
cramps and proximal weakness, mimicking an acquired myopathy. Muscle biopsy
disclosed slight alterations in one sample and severe dystrophic changes in
another; dystrophin was absent in 7% fibers in the former specimen and in 60% in
the second. X inactivation was skewed with 90% cells inactivating the same X
chromosome. The second patient was a 17- year- old girl with hyperCKemia, learning
disability and a family history of X- linked muscular dystrophy. Muscle biopsy
displayed slight fiber size variability and some internal nuclei; dystrophin was
absent only in one muscle fiber. A second sample with the same morphological
features demonstrated dystrophin deficiency with mosaic distribution. The
pattern of X inactivation was normal. These cases emphasize the variability of
histopathological changes and dystrophin deficiency in Xp21 muscular dystrophy
carriers and the risk of sampling errors in muscle biopsy.
PMID: 10378386 [PubMed - indexed for MEDLINE]
9: Clin Genet 1999 May;55(5):362- 6
Characterisation, phenotypic manifestations and X- inactivation pattern in 14
patients with X- autosome translocations.
Kalz- Fuller B, Sleegers E, Schwanitz G, Schubert R.
Institute of Human Genetics, University of Bonn, Germany.
cytogen@humgen.uni- bonn.de
Here we describe a group of 14 patients carrying different X- autosome
translocations and exhibiting phenotypes that demonstrate the range of
alterations induced by such aberrations. All male carriers of an X- autosome
translocation in our investigation group were infertile, whereas fertility in
the female carriers was dependent on the position of the break- point in the X
chromosome. Fertile women with translocation break- points outside of the
critical region (Xq13- q26) in some cases passed on the translocation to their
offspring. In balanced female carriers in our group, the normal X chromosome was
usually inactivated, allowing full expression of genes on the translocated
segments. In one case, disruption of the dystrophine gene in Xp21 led to the
manifestation of Duchenne muscular dystrophy in a female carrier. Inactivation
of the derivative X (Xt) in a balanced female carrier led to a partial monosomy
of the autosome/disomy of the X chromosome and resulted in an aberrant
phenotype. In unbalanced carriers, Xt is generally late- replicating/inactive,
although failed spreading of inactivation to the autosomal segment often results
in a partial trisomy, as evidenced by the case of an unbalanced translocation
carrier in our group.
PMID: 10422808 [PubMed - indexed for MEDLINE]
10: Hum Genet 1999 Mar;104(3):249- 53
Skewed X- inactivation in a manifesting carrier of X- linked myotubular myopathy
and in her non- manifesting carrier mother.
Tanner SM, Orstavik KH, Kristiansen M, Lev D, Lerman- Sagie T, Sadeh M,
Liechti- Gallati S.
Department of Clinical Research, Human Molecular Genetics, Children's Hospital,
University of Berne, Switzerland. tanner- 1@medctr.osu.edu
X- linked recessive myotubular myopathy (XLMTM) is a muscle disorder usually
affecting newborn males. In the majority of cases, muscle weakness and hypotonia
lead to a rapid demise at neonatal age. The responsible MTM1 gene is located in
proximal Xq28. Heterozygous carriers are described as being asymptomatic but, in
a few cases, mild facial weakness has been reported. We report a family in which
a 39- year old female showed severe progressive muscle weakness. XLMTM was
initially diagnosed in the male offspring of one of the patient's sisters. The
patient, one of her sisters, and their mother were heterozygous carriers for a
common MTM1 gene mutation. We found an extremely skewed X- inactivation pattern
in the patient and, in the opposite direction, in her non- manifesting carrier
mother, thus explaining her normal phenotype and indicating a possible
inheritance of skewed X- inactivation. Linkage analysis excluded a possible
involvement of the XIST locus at Xq13.
PMID: 10323249 [PubMed - indexed for MEDLINE]
11: Am J Med Genet 1998 Dec 4;80(4):356- 61
Absence of correlation between skewed X inactivation in blood and serum
creatine- kinase levels in Duchenne/Becker female carriers.
Sumita DR, Vainzof M, Campiotto S, Cerqueira AM, Canovas M, Otto PA,
Passos- Bueno MR, Zatz M.
Departamento de Biologia, Instituto de Biociencias, Universidade de Sao Paulo,
SP, Brazil.
The pattern of X inactivation in lymphocyte DNA was investigated in 107 Duchenne
muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) carriers (102
asymptomatic and 5 manifesting carriers) and 117 normal female controls of
different ages, with the aim: a) to analyze the pattern of X inactivation in
blood DNA of a large number of DMD/BMD carriers as compared to normal female
controls; b) to determine if there is a decrease in serum creatine kinase (CK)
levels with age in obligate DMD/BMD carriers; c) to determine if there is a
correlation between X- chromosome inactivation and serum CK among asymptomatic
DMD/BMD carriers of different ages or with different clinical manifestations in
symptomatic carriers. A high proportion of females showed extremely skewed X
inactivation (more than 90% of one X preferentially inactivated), which was almost the
same among carriers and normal controls (19 and 24%, respectively). The mean
serum CK was significantly greater among young (less than 20 years old) than adult (more than 20
years old) DMD/BMD carriers and it decreased significantly until age 20 with an
apparent stabilization afterwards. No statistically significant correlation was
found between the proportion of active X(DMD) in blood and serum CK activity in
DMD/BMD carriers although it was higher among those less than 20 years old. Our
observations suggest that highly skewed X- chromosome pattern in blood (with
preferential inactivation of the X(N) chromosome) is not enough to predict that
a young DMD carrier will develop muscular weakness.
PMID: 9856563 [PubMed - indexed for MEDLINE]
12: Neuromuscul Disord 1998 Dec;8(8):585- 90
Cardiac transplantation in a Duchenne muscular dystrophy carrier.
Melacini P, Fanin M, Angelini A, Pegoraro E, Livi U, Danieli GA, Hoffman EP,
Thiene G, Dalla Volta S, Angelini C.
Department of Cardiology, University of Padua, Italy.
We report here for the first time the case of a symptomatic DMD carrier, who had
a heart transplant for a severe dilated cardiomyopathy. Dystrophin
immunohistochemistry, western blot and analysis of X- chromosome inactivation on
leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were
performed. The patient was a heterozygote for exons 50- 52 deletion in the
dystrophin gene. The number of dystrophin- deficient fibres in the heart was much
higher than in skeletal muscle. On the other hand, the explanted heart showed a
non- skewed pattern of X- chromosome inactivation, as in leukocytes and skeletal
muscle. The adverse cardiac course may be explained by the absence of
regeneration among cardiomyocytes.
PMID: 10093066 [PubMed - indexed for MEDLINE]
13: Am J Hum Genet 1998 Nov;63(5):1457- 63
X chromosome inactivation in carriers of Barth syndrome.
Orstavik KH, Orstavik RE, Naumova AK, D'Adamo P, Gedeon A, Bolhuis PA, Barth PG,
Toniolo D.
Department of Medical Genetics, Ulleval University Hospital, Oslo, Norway.
k.h.orstavik@ioks.uio.no
Barth syndrome (BTHS) is a rare X- linked recessive disorder characterized by
cardiac and skeletal myopathy, neutropenia, and short stature. A gene for BTHS,
G4.5, was recently cloned and encodes several novel proteins, named "tafazzins."
Unique mutations have been found. No correlation between the location or type of
mutation and the phenotype of BTHS has been found. Female carriers of BTHS seem
to be healthy. This could be due to a selection against cells that have the
mutant allele on the active X chromosome. We therefore analyzed X chromosome
inactivation in 16 obligate carriers of BTHS, from six families, using PCR in
the androgen- receptor locus. An extremely skewed X- inactivation pattern
(>=95:5), not found in 148 female controls, was found in six carriers. The
skewed pattern in two carriers from one family was confirmed in DNA from
cultured fibroblasts. Five carriers from two families had a skewed pattern
(80:20- <95:5), a pattern that was found in only 11 of 148 female controls. Of
the 11 carriers with a skewed pattern, the parental origin of the inactive X
chromosome was maternal in all seven cases for which this could be determined.
In two families, carriers with an extremely skewed pattern and carriers with a
random pattern were found. The skewed X inactivation in 11 of 16 carriers is
probably the result of a selection against cells with the mutated gene on the
active X chromosome. Since BTHS also shows great clinical variation within
families, additional factors are likely to influence the expression of the
phenotype. Such factors may also influence the selection mechanism in carriers.
PMID: 9792874 [PubMed - indexed for MEDLINE]
14: Hum Mol Genet 1998 May;7(5):855- 64
Mutations in Emery- Dreifuss muscular dystrophy and their effects on emerin
protein expression.
Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Llense S, Leturcq F, Deburgrave N,
Barbot J, Man N, Muntoni F, Wehnert M, Kaplan J, Morris GE.
MRIC Biochemistry Group, NE Wales Institute, Wrexham LL11 2AW, UK.
Seventeen families with Emery- Dreifuss muscular dystrophy (EDMD) have been
studied both by DNA sequencing and by emerin protein expression. Fourteen had
mutations in the X- linked emerin gene, while three showed evidence of autosomal
inheritance. Twelve of the 14 emerin mutations caused early termination of
translation. An in- frame deletion of six amino acids from the C- terminal
transmembrane helix caused almost complete absence of emerin from muscle with no
localization to the nuclear membrane, although mRNA levels were normal. This
shows that mutant emerin proteins are unstable if they are unable to integrate
into a membrane. A 22 bp deletion in the promoter region was expected to result
in reduced emerin production, but normal amounts of emerin of normal size were
found in leucocytes and lymphoblastoid cell lines. This shows that DNA analysis
is necessary to exclude emerin mutations in suspected X- linked EDMD. Emerin
levels in female carriers often deviated from the expected 50% and this was due,
in at least two families, to skewed emerin mRNA expression from the normal and
mutated alleles. In one family with a novel deletion of the last three exons of
the emerin gene, a carrier had a cardiomyopathy and very low emerin levels (<5%
of normal) due to skewed X- inactivation. In the three autosomal cases of EDMD,
emerin was normal on western blots of blood cells, which suggests that autosomal
EDMD is not caused by indirect reduction of emerin levels.
PMID: 9536090 [PubMed - indexed for MEDLINE]
15: Clin Genet 1998 Feb;53(2):102- 7
Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy.
Yoshioka M, Yorifuji T, Mituyoshi I.
Department of Pediatrics, Kobe General Hospital, Japan.
We studied X inactivation patterns in manifesting carriers of familial and
sporadic Duchenne muscular dystrophy (DMD) or unaffected carriers of DMD by
analysis of the methylation of HpaII sites in the first exon of the human
androgen- receptor gene (HUMARA) from peripheral blood samples. Three of the four
manifesting carriers, four of the five asymptomatic carriers, and 31 of the 32
female controls were heterozygous for the CAG repeat of HUMARA. All manifesting
carriers showed skewed X inactivation, while all unaffected carriers showed
almost symmetrical inactivation. One family studied over three generations is
noteworthy because it includes two mother/daughter pairs, one an affected pair
with skewed X inactivation, and the other a phenotypically normal carrier pair
with random X inactivation. On the other hand, the extent of X inactivation for
each X chromosome in 31 female controls was widely distributed. These data
suggest that in carriers of DMD, both affected and unaffected, it is valuable to
analyze the pattern of skewed X inactivation because it provides important
prognostic information. Carriers of DMD with skewed X inactivation might show
slowly progressive myopathy with advancing age.
PMID: 9611069 [PubMed - indexed for MEDLINE]
16: Am J Hum Genet 1997 Jul;61(1):160- 70
Comment in:
Am J Hum Genet. 1998 Jun;62(6):1555- 7; discussion 1557- 8.
Familial skewed X inactivation: a molecular trait associated with high
spontaneous- abortion rate maps to Xq28.
Pegoraro E, Whitaker J, Mowery- Rushton P, Surti U, Lanasa M, Hoffman EP.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh
School of Medicine, PA 15261, USA.
We report a family ascertained for molecular diagnosis of muscular dystrophy in
a young girl, in which preferential activation (> or = 95% of cells) of the
paternal X chromosome was seen in both the proband and her mother. To determine
the molecular basis for skewed X inactivation, we studied X- inactivation
patterns in peripheral blood and/or oral mucosal cells from 50 members of this
family and from a cohort of normal females. We found excellent concordance
between X- inactivation patterns in blood and oral mucosal cell nuclei in all
females. Of the 50 female pedigree members studied, 16 showed preferential use
(> or = 95% cells) of the paternal X chromosome; none of 62 randomly selected
females showed similarly skewed X inactivation was maternally inherited in this
family. A linkage study using the molecular trait of skewed X inactivation as
the scored phenotype localized this trait to Xq28 (DXS1108; maximum LOD score
[Zmax] = 4.34, recombination fraction [theta] = 0). Both genotyping of
additional markers and FISH of a YAC probe in Xq28 showed a deletion spanning
from intron 22 of the factor VIII gene to DXS115- 3. This deletion completely
cosegregated with the trait (Zmax = 6.92, theta = 0). Comparison of clinical
findings between affected and unaffected females in the 50- member pedigree
showed a statistically significant increase in spontaneous- abortion rate in the
females carrying the trait (P less than .02). To our knowledge, this is the first
gene- mapping study of abnormalities of X- inactivation patterns and is the first
association of a specific locus for recurrent spontaneous abortion in a
cytogenetically normal family. The involvement of this locus in cell lethality,
cell- growth disadvantage, developmental abnormalities, or the X- inactivation
process is discussed.
PMID: 9245997 [PubMed - indexed for MEDLINE]
17: Am J Hum Genet 1997 Jan;60(1):160- 5
Uniparental disomy of the entire X chromosome in a female with Duchenne muscular
dystrophy.
Quan F, Janas J, Toth- Fejel S, Johnson DB, Wolford JK, Popovich BW.
DNA Diagnostic Laboratory, Oregon Health Sciences University, Portland 97201,
USA.
Duchenne muscular dystrophy (DMD) is a severe, progressive, X- linked
muscle- wasting disorder with an incidence of approximately 1/3,500 male births.
Females are also affected, in rare instances. The manifestation of mild to
severe symptoms in female carriers of dystrophin mutations is often the result
of the preferential inactivation of the X chromosome carrying the normal
dystrophin gene. The severity of the symptoms is dependent on the proportion of
cells that have inactivated the normal X chromosome. A skewed pattern of X
inactivation is also responsible for the clinical manifestation of DMD in
females carrying X;autosome translocations, which disrupt the dystrophin gene.
DMD may also be observed in females with Turner syndrome (45,X), if the
remaining X chromosome carries a DMD mutation. We report here the case of a
karyotypically normal female affected with DMD as a result of homozygosity for a
deletion of exon 50 of the dystrophin gene. PCR analysis of microsatellite
markers spanning the length of the X chromosome demonstrated that homozygosity
for the dystrophin gene mutation was caused by maternal isodisomy for the entire
X chromosome. This finding demonstrates that uniparental isodisomy of the X
chromosome is an additional mechanism for the expression of X- linked recessive
disorders. The proband's clinical presentation is consistent with the absence of
imprinted genes (i.e., genes that are selectively expressed based on the parent
of origin) on the X chromosome.
PMID: 8981959 [PubMed - indexed for MEDLINE]
18: Neurology 1996 Apr;46(4):1189- 91
Comment on:
Neurology. 1995 Apr;45(4):677- 90.
Pattern of X- chromosome inactivation as a key determinant of the
clinicopathologic phenotype of Duchenne muscular dystrophy carriers.
Matthews PM, Karpati G.
Publication Types:
Comment
Letter
PMID: 8780133 [PubMed - indexed for MEDLINE]
19: J Cell Biochem Suppl 1996;25:29- 36
Cancer risk factors for selecting cohorts for large- scale chemoprevention
trials.
Greenwald P.
Division of Cancer Prevention and Control, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892, USA. GreenwaP@DCPC31.NCI.NIH.GOV
Many anticipate that application of findings in molecular genetics will help to
achieve greater precision in defining high- risk populations that may benefit
from chemopreventive interventions. We must recognize, however, that genetic
susceptibility, environmental factors, and complex gene- environment interactions
are all likely to be risk determinants for most cancers. Cohort studies of twins
and cancer indicate that having "identical" genes is generally not a very
accurate predictor of cancer incidence. Data from twin studies support the
suggestion that environmental factors such as tobacco use significantly
influence cancer risk. The complexities of the genetic contribution to disease
risk are exemplified by the development of Duchenne muscular dystrophy in only
one of monozygotic twin girls, hypothesized to be the result of X chromosome
inactivation, with the distribution patterns of the X chromosome being skewed to
the female X in the manifesting twin and to the male X in the normal twin.
Evidence from transgenic and genetic- environmental studies in animals support
the possibility of genetic- environmental interactions. Calorie restriction
modifies tumor expression in p53 knockout mice; a high- fat, low- calcium,
low- vitamin D diet increases prepolyp hyperplasia formation in Apc- mutated mice;
and calorie restriction early in life influences development of obesity in the
genetically obese Zucker rat (fafa). Such environmental modulation of gene
expression suggests that chemoprevention has the potential to reduce risk for
both environmentally and genetically determined cancers. In view of the growing
research efforts in chemoprevention, the NCI has developed a Prevention Trials
Decision Network (PTDN) to formalize the evaluation and approval process for
large- scale chemoprevention trials. The PTDN addresses large trial
prioritization and the associated issues of minority recruitment and retention;
identification and validation of biomarkers as intermediate endpoints for
cancer; and chemopreventive agent selection and development. A comprehensive
database is being established to support the PTDN's decision- making process and
will help to determine which agents investigated in preclinical and early phase
clinical trials should move to large- scale testing. Cohorts for large- scale
chemoprevention trials include individuals who are determined to be at high risk
as a result of genetic predisposition, carcinogenic exposure, or the presence of
biomarkers indicative of increased risk. Current large- scale trials in
well- defined, high- risk populations include the Breast Cancer Prevention Trial
(tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the
N- (4- hydroxyphenyl) retinamide (4- HPR) breast cancer prevention study being
conducted in Milan. Biomarker studies will provide valuable information for
refining the design and facilitating the implementation of future large- scale
trials. For example, potential biomarkers are being assessed at biopsy in women
with ductal carcinoma in situ (DCIS). The women are then randomized to either
placebo, tamoxifen, 4- HPR, or tamoxifen plus 4- HPR for 2- 4 weeks, at which time
surgery is performed and the biomarkers reassessed to determine biomarker
modulation by the interventions. For prostate cancer, modulation of prostatic
intraepithelial neoplasia (PIN) by 4- HPR and difluoromethylornithine is being
investigated; similar studies are being planned for oltipraz,
dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of
biomarkers as surrogate endpoints for cancer incidence in high- risk cohorts will
allow more agents to be evaluated in shorter studies that use fewer subjects to
achieve the desired statistical power.
Publication Types:
Review
Review, Tutorial
PMID: 9027595 [PubMed - indexed for MEDLINE]
20: Hum Genet 1995 Aug;96(2):167- 76
X- chromosome methylation in manifesting and healthy carriers of
dystrophinopathies: concordance of activation ratios among first degree female
relatives and skewed inactivation as cause of the affected phenotypes.
Azofeifa J, Voit T, Hubner C, Cremer M.
Institut fur Humangenetik und Anthropologie, Universitat Heidelberg, Germany.
The X- chromosome activity states of 11 manifesting carriers of
dystrophinopathies, all with normal karyotypes, were estimated by restriction
fragment length polymorphism (RFLP)- methylation analysis with the probes M27
beta (DXS255), p2- 19(DXS605) and pSPT/PGK (PGK1) to test the role of skewed
X- inactivation ratios as the cause of their affected phenotypes. In eight cases
preferential inactivation of the putative X chromosome carrying the normal
dystrophin allele in greater than or = 90% of their peripheral lymphocytes was observed,
two cases showed non- apparent deviant ratios (60:40 and 70:30) from the
theoretically expected values around the mean of 50% and in one case the three
markers employed yielded no information. The analysis of the X- inactivation
ratio in six mother- daughter pairs, all non- manifesting Duchenne muscular
dystrophy (DMD) carriers, and in the close female relatives of the patients
showed: (a) neither of the two X chromosomes was preferentially inactivated with
respect to their parental origin; (b) a high concordance among the activation
ratios of mothers and daughters, a result difficult to explain just in terms of
random X- chromosome inactivation.
PMID: 7635465 [PubMed - indexed for MEDLINE]
21: Neurology 1995 Jul;45(7):1409- 10
Transmission of dystrophinopathy by X- chromosome inversion.
Konagaya M, Honda H, Sakai M, Iida M.
Department of Neurology, Suzuka National Hospital, Japan.
A woman had a karyotype of 46Xinv(X)(p21.2;q26.1) and mosaicism of
dystrophin- negative muscle fibers. The X- chromosome inversion was transmitted to
her daughter, who had an elevated serum CK. The genetic transmission as well as
the probable random inactivation of the abnormal X chromosome in this mildly
affected patient distinguish this case from those of dystrophinopathy with
X;autosome translocations.
PMID: 7617206 [PubMed - indexed for MEDLINE]
22: Am J Hum Genet 1995 May;56(5):1108- 15
Myotubular myopathy in a girl with a deletion at Xq27- q28 and unbalanced X
inactivation assigns the MTM1 gene to a 600- kb region.
Dahl N, Hu LJ, Chery M, Fardeau M, Gilgenkrantz S, Nivelon- Chevallier A,
Sidaner- Noisette I, Mugneret F, Gouyon JB, Gal A, et al.
Laboratorire de Genetique Moleculaire des Eucaryotes du CNRS, INSERM U184,
Strasbourg, France.
A young girl with a clinically moderate form of myotubular myopathy was found to
carry a cytogenetically detectable deletion in Xq27- q28. The deletion had
occurred de novo on the paternal X chromosome. It encompasses the fragile X
(FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in
Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49,
DXS256, DXS258, DXS305, and DXS497) were found intact. As the X- linked
myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage
analysis, the present observation suggested that MTM1 is included in the
deletion. However, a significant clinical phenotype is unexpected in a female
MTM1 carrier. Analysis of inactive X- specific methylation at the androgen
receptor gene showed that the deleted X chromosome was active in approximately
80% of leukocytes. Such unbalanced inactivation may account for the moderate
MTM1 phenotype and for the mental retardation that later developed in the
patient. This observation is discussed in relation to the hypothesis that a
locus modulating X inactivation may lie in the region. Comparison of this
deletion with that carried by a male patient with a severe Hunter syndrome
phenotype but no myotubular myopathy, in light of recent linkage data on
recombinant MTM1 families, led to a considerable refinement of the position of
the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.
PMID: 7726166 [PubMed - indexed for MEDLINE]
23: Neuromuscul Disord 1995 May;5(3):209- 20
Muscle X- inactivation patterns and dystrophin expression in Duchenne muscular
dystrophy carriers.
Matthews PM, Benjamin D, Van Bakel I, Squier MV, Nicholson LV, Sewry C, Barnes
PR, Hopkin J, Brown R, Hilton- Jones D, et al.
Genetics Laboratory, University of Oxford, U.K.
Muscle pathology, dystrophin expression and X- inactivation patterns were studied
in the muscle of five asymptomatic females heterozygous for deletions in the
dystrophin gene (non- manifesting carriers) and five symptomatic carriers
(manifesting carriers). Muscle from the non- manifesting carriers showed an
increase in the population of centrally nucleated fibres (9.0 +/- 2.8%;
controls, 1.4 +/- 0.3%), frequent fibers with abnormally interrupted dystrophin
staining (38 +/- 5%), and, in sections from three individuals, small numbers of
dystrophin- negative fibers (1- 4%). The amount of dystrophin measured by
immunoblotting was reduced to 64 +/- 5% (P < 0.001 n = 5) of normal. The pattern
of X- inactivation in muscle DNA was non- biased (50: 50- 60: 40) in all cases. In
the manifesting carriers both highly biased (90: 10) and non- biased patterns of
X- inactivation were found, but no consistent relationship was apparent between
the patterns of X- inactivation and the proportions of dystrophin- negative
fibers. We conclude from studies of the non- manifesting carriers that the
proportion of residual dystrophin is similar to the relative activation in
muscle of the X- chromosome carrying the wild- type allele. Extreme bias of
X- inactivation can be associated with early clinical symptoms and severe
pathology. However, as non- manifesting and some manifesting adult carriers had
identical patterns of X- inactivation, abnormalities in the distribution of
dystrophin, as well as overall levels of expression, may be important for the
development of myopathic pathology.
PMID: 7633186 [PubMed - indexed for MEDLINE]
24: Neurology 1995 Apr;45(4):677- 90
Comment in:
Neurology. 1996 Apr;46(4):1189- 91.
Genetic and biochemical normalization in female carriers of Duchenne muscular
dystrophy: evidence for failure of dystrophin production in dystrophin- competent
myonuclei.
Pegoraro E, Schimke RN, Garcia C, Stern H, Cadaldini M, Angelini C, Barbosa E,
Carroll J, Marks WA, Neville HE.
Department of Molecular Genetics, University of Pittsburgh School of Medicine,
PA 15216, USA.
We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy
(DMD) gene. Most of these dystrophinopathy patients had had an erroneous or
ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed
clinical severity by a standardized protocol, measured X- chromosome inactivation
patterns in blood and muscle DNA, and quantitated the dystrophin protein content
of muscle. We found that patients could be separated into two groups: those
showing equal numbers of normal and mutant dystrophin genes in peripheral blood
DNA ("random" X- inactivation), and those showing preferential use of the mutant
dystrophin gene ("skewed" X- inactivation). In the random X- inactivation
carriers, the clinical phenotype ranged from asymptomatic to mild disability,
the dystrophin content of muscle was > 60% of normal, and there were only minor
histopathologic changes. In the skewed X- inactivation patients, clinical
manifestations ranged from mild to severe, but the patients with mild disease
were young (5 to 10 years old). The low levels of dystrophin (< 30% on average)
and the severe symptoms of the older patients suggested a poor prognosis for
those with skewed X- inactivation, and they all showed morphologic changes of
dystrophy. The random inactivation patients showed evidence of biochemical
"normalization," with higher dystrophin content in muscle than predicted by the
number of normal dystrophin genes. Seventy- nine percent of skewed X- inactivation
patients (11/14) showed genetic "normalization," with proportionally more
dystrophin- positive nuclei in muscle than in blood. In 65% of the skewed
X- inactivation patients, dystrophin was not produced by dystrophin- positive
nuclei; an average of 20% of myofiber nuclei were genetically
dystrophin- positive but did not produce stable dystrophin. Biochemical
normalization seems to be the main mechanism for rescue of fibers from
dystrophin deficiency in the random X- inactivation patients. In the skewed
X- inactivation patients, genetic normalization is active, but production failure
of dystrophin by dystrophin- normal nuclei may counteract any effect of
biochemical normalization. In the skewed X- inactivation patients, the remodeling
of the muscle through cycles of degeneration and regeneration led to threefold
increase in the number of dystrophin- competent nuclei in muscle myofibers (3.3
+/- 4.6), while dystrophin content was on the average 1.5- fold less then
expected (- 1.54 +/- 3.38). Our results permit more accurate prognistic
assessment of isolated female dystrophinopathy patients and provide important
data with which to estimate the potential effect of gene delivery (gene therapy)
in DMD.
PMID: 7723955 [PubMed - indexed for MEDLINE]
25: Southeast Asian J Trop Med Public Health 1995;26 Suppl 1:166- 71
Duchenne muscular dystrophy.
Matsuo M.
International Center for Medical Research, Kobe University School of Medicine,
Japan.
Duchenne muscular dystrophy (DMD) is a common inherited disease with a worldwide
incidence of 1 in 3,500 male births. Recent molecular study on the DMD gene
identified a 14- kb mRNA encoded by 79 exons distributed over 2.5 million bp of
the X- chromosome. The protein named dystrophin contains 3,685 amino acids. Most
of the genetic events (mutations) that inactivate the dystrophin gene have been
shown to be deletions, with over 65% of patients exhibiting the loss of one or
more of the exons at the genomic DNA level. The mechanism of the inactivation of
the dystrophin gene in one third of patients with DMD/BMD is unknown.
Publication Types:
Review
Review, Tutorial
PMID: 8629099 [PubMed - indexed for MEDLINE]
26: Circulation 1994 Sep;90(3):1350- 6
Reduction of the transient outward potassium current in canine X- linked muscular
dystrophy.
Pacioretty LM, Cooper BJ, Gilmour RF Jr.
Department of Physiology, College of Veterinary Medicine, Cornell University,
Ithaca, NY 14853- 6401.
BACKGROUND: The xmd dog develops a cardiomyopathy similar to that seen in
Duchenne muscular dystrophy patients. In both the canine and human diseases, ECG
abnormalities may precede the development of overt cardiac pathological lesions.
The purpose of this study was to determine whether specific cellular electrical
abnormalities occur in dystrophic ventricular tissue. METHODS AND RESULTS:
Action potentials were recorded in epicardial tissue strips obtained from normal
and xmd dogs. Phase 1 amplitude was increased from 86.8 +/- 2.7 mV in normal
dogs to 94.3 +/- 1.8 mV in xmd dogs (mean +/- SEM; P < .05). The
4- aminopyridine- sensitive transient outward potassium current (Ito), as recorded
in isolated epicardial myocytes using the whole- cell patch- clamp technique, was
reduced in xmd dogs compared with age- matched normal dogs. Cell capacitance also
was reduced significantly in xmd compared with normal cells, as was the current
density (3.6 +/- 0.3 versus 5.4 +/- 0.8 pA/pF, respectively). No differences
were observed in the time constants of current decay or in the kinetics of
recovery from inactivation between groups. The slope factor (k) of steady- state
inactivation was significantly greater in xmd compared with normal cells (7.2
+/- 0.9 versus 5.4 +/- 0.5, respectively), whereas the V1/2 of inactivation did
not differ (- 38.2 +/- 2.4 versus - 36.8 +/- 1.6 mV, respectively). CONCLUSIONS:
These data indicate that the magnitude of Ito is reduced in dystrophic
epicardial myocytes, resulting in an increase in phase 1 amplitude. The
reduction of Ito may alter the balance of inward and outward currents in
dystrophic myocardium and thereby contribute to the development of cardiac
pathology.
PMID: 8087945 [PubMed - indexed for MEDLINE]
27: Am J Med Genet 1994 Aug 15;52(2):198- 206
Additional case of female monozygotic twins discordant for the clinical
manifestations of Duchenne muscular dystrophy due to opposite X- chromosome
inactivation.
Abbadi N, Philippe C, Chery M, Gilgenkrantz H, Tome F, Collin H, Theau D, Recan
D, Broux O, Fardeau M, et al.
Laboratoire de Genetique Universite de Nancy, France.
A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in
the DMD gene and discordant for the clinical manifestations of Duchenne muscular
dystrophy, were analyzed by molecular studies, in situ hybridization, and
methylation pattern of X chromosomes to search for opposite X inactivation as an
explanation of their clinical discordance. Results in lymphocytes and skin
fibroblast cell lines suggest a partial mirror inactivation with the normal X
chromosome preferentially active in the unaffected twin, and the maternal
deleted X chromosome preferentially active in the affected twin. A review shows
that MZ female twins discordant for X- linked diseases are not uncommon. Twinning
and X inactivation may be interrelated and could explain the female twins
discordant for X- linked traits.
PMID: 7802009 [PubMed - indexed for MEDLINE]
28: Am J Hum Genet 1994 Jun;54(6):989- 1003
Detection of new paternal dystrophin gene mutations in isolated cases of
dystrophinopathy in females.
Pegoraro E, Schimke RN, Arahata K, Hayashi Y, Stern H, Marks H, Glasberg MR,
Carroll JE, Taber JW, Wessel HB, et al.
Department of Molecular Genetics, University of Pittsburgh, School of Medicine,
PA 15261.
Duchenne muscular dystrophy is one of the most common lethal monogenic disorders
and is caused by dystrophin deficiency. The disease is transmitted as an
X- linked recessive trait; however, recent biochemical and clinical studies have
shown that many girls and women with a primary myopathy have an underlying
dystrophinopathy, despite a negative family history for Duchenne dystrophy.
These isolated female dystrophinopathy patients carried ambiguous diagnoses with
presumed autosomal recessive inheritance (limb- girdle muscular dystrophy) prior
to biochemical detection of dystrophin abnormalities in their muscle biopsy. It
has been assumed that these female dystrophinopathy patients are heterozygous
carriers who show preferential inactivation of the X chromosome harboring the
normal dystrophin gene, although this has been shown for only a few X:autosome
translocations and for two cases of discordant monozygotic twin female carriers.
Here we study X- inactivation patterns of 13 female dystrophinopathy patients-- 10
isolated cases and 3 cases with a positive family history for Duchenne dystrophy
in males. We show that all cases have skewed X- inactivation patterns in
peripheral blood DNA. Of the nine isolated cases informative in our assay, eight
showed inheritance of the dystrophin gene mutation from the paternal germ line.
Only a single case showed maternal inheritance. The 10- fold higher incidence of
paternal transmission of dystrophin gene mutations in these cases is at 30- fold
variance with Bayesian predictions and gene mutation rates. Thus, our results
suggest some mechanistic interaction between new dystrophin gene mutations,
paternal inheritance, and skewed X inactivation. Our results provide both
empirical risk data and a molecular diagnostic test method, which permit genetic
counseling and prenatal diagnosis of this new category of patients.
PMID: 8198142 [PubMed - indexed for MEDLINE]
29: Hum Genet 1994 May;93(5):563- 7
Skewed inactivation of an X chromosome deleted at the dystrophin gene in an
asymptomatic mother and her affected daughter.
Tihy F, Vogt N, Recan D, Malfoy B, Leturcq F, Coquet M, Serville F, Fontan D,
Guillard JM, Kaplan JC, et al.
Universite de Montreal, Departement de Pathologie, Faculte de Medecine, Canada.
A girl with severe Becker muscular dystrophy and apparently normal chromosomes
had a heterozygous deletion for exons 51, 52, and 53 of the dystrophin gene.
This deletion was transmitted by her mother, who was unaffected. To
differentiate the normal and the deleted X chromosomes, fluorescence in situ
hybridization (FISH) was applied to metaphase chromosomes, using probes for both
exons 51 and 52, which are only 388 and 113 base pairs long, respectively. FISH
signals were observed in one or both chromatids of one chromosome, but never on
both chromosomes, suggesting the lack of hybridization on the deleted X
chromosome. Using 5- bromodeoxyuridine incorporation to differentiate the late
(inactive) and the early replicating (active) X chromosomes, 77% of the signals
were observed on the active X chromosomes in the mother. This percentage was
only 18% in the daughter, suggesting that skewed inactivation of the X
chromosomes was responsible for the phenotypic differences.
PMID: 8168835 [PubMed - indexed for MEDLINE]
30: Acta Genet Med Gemellol (Roma) 1994;43(3- 4):207- 14
MZ female twins discordant for X- linked diseases: a review.
Tiberio G.
Centro Pediatrico Internazionale Luigi Gedda, Gregor Mendel Institute, Rome.
The 20 reported cases of MZ female twins discordant for X- linked diseases are
reviewed. In such twins the X- inactivation pattern is opposite skewing (abnormal
allele inactivated in most cells of the normal twin, and normal allele
inactivated in most cells of the affected twin) or skewing in one twin and
random in the cotwin. The diseases involved map in two specific regions: Xq27- 28
and Xp21. The only exceptions are Fabry's disease and Aicardi's syndrome, which
map in Xq22 and Xp22 respectively. No concordant MZ female carrier twins, either
normal or affected, have been described. Three main hypotheses have been
proposed to explain such characteristics [2, 5, 14], but none is completely
satisfactory. The constant discordance for X- linked diseases in MZ female twins
has important consequences for genetic counselling.
Publication Types:
Review
Review of Reported Cases
Twin Study
PMID: 8588495 [PubMed - indexed for MEDLINE]
31: Am J Med Genet 1993 Mar 1;45(5):601- 5
In situ hybridization shows direct evidence of skewed X inactivation in one of
monozygotic twin females manifesting Duchenne muscular dystrophy.
Zneimer SM, Schneider NR, Richards CS.
University of Texas Southwestern Medical Center, Department of Pathology,
Dallas.
A novel combination of conventional and molecular cytogenetic techniques was
used to investigate the expression of an X- linked recessive disorder in one of
monozygotic (MZ) twin females. These twins carry a deletion, approximately 300
kb in length, in one of their X chromosomes within the dystrophin gene, which is
responsible for Duchenne muscular dystrophy (DMD) in one twin [Richards et al.:
Am J Hum Genet 46:672- 681, 1990]. A unique DNA fragment generated from an exon
within this gene deletion was hybridized in situ to both twins' metaphase
chromosomes, a probe which would presumably hybridize only to the normal X
chromosome and not to the X chromosome carrying the gene deletion. Chromosomes
were identified by reverse- banding (R- banding) and by the addition of
5- bromodeoxyuridine (BrdU) in culture to distinguish early and late replicating
X chromosomes, corresponding to active and inactive X chromosomes, respectively.
Hybridization experiments showed predominant inactivation of the normal X
chromosome in the twin with DMD. This is the first report showing direct
evidence at the chromosome level of unequal inactivation of cytogenetically
normal X chromosomes resulting in the manifestation of an X- linked recessive
disorder in one of monozygotic twin females. This study may now facilitate other
research of unequal X inactivation and of females manifesting X- linked recessive
disorders.
PMID: 8456832 [PubMed - indexed for MEDLINE]
32: Neuromuscul Disord 1993 Jan;3(1):57- 64
Variability in clinical, genetic and protein abnormalities in manifesting
carriers of Duchenne and Becker muscular dystrophy.
Bushby KM, Goodship JA, Nicholson LV, Johnson MA, Haggerty ID, Gardner- Medwin D.
Department of Human Genetics, University of Newcastle upon Tyne, U.K.
We have analysed the results of clinical assessment, X- inactivation status,
deletion screening and dystrophin analysis in eight manifesting carriers of
Duchenne and Becker muscular dystrophy (DMD and BMD). Only two had a prior
family history of X- linked muscle disease, all had normal karyotypes and none
were twins. Presentation varied from 2 to 25 yr and progression varied from a
DMD- like severity to a very mild BMD- like course. In one girl the initial
symptoms were restricted to learning difficulties. Where methods for assessing
X- inactivation were informative, three patients showed an abnormal pattern.
However, in one patient, the obligate carrier daughter of a BMD patient who had
presented at the age of 2 yr, X- inactivation appeared normal in lymphocytes and
muscle. While dystrophin analysis seems to be reliable in identifying
manifesting carriers of DMD and BMD, the relationship between X- inactivation
status, dystrophin analysis and phenotype is not simple.
PMID: 8329890 [PubMed - indexed for MEDLINE]
33: Am J Med Genet 1992 Dec 1;44(6):834- 8
Female twin with Hunter disease due to nonrandom inactivation of the
X- chromosome: a consequence of twinning.
Winchester B, Young E, Geddes S, Genet S, Hurst J, Middleton- Price H, Williams
N, Webb M, Habel A, Malcolm S.
Division of Biochemistry and Metabolism, Institute of Child Health, London, U.K.
We report the occurrence of Hunter disease (mucopolysaccharidosis type II) in a
karyotypically normal girl who was one of identical twins. Molecular studies
showed nonrandom X- inactivation in both her fibroblasts and lymphocytes, while
her normal twin showed equal usage of both X chromosomes. In view of previous
reports of 7 pairs of identical female twins in which one had Duchenne muscular
dystrophy, it seems that twinning may be strongly associated with nonrandom
X- inactivation, and is not specific to the properties of the disease causing
gene.
Publication Types:
Review
Review of Reported Cases
PMID: 1481858 [PubMed - indexed for MEDLINE]
34: Am J Med Genet 1992 Aug 1;43(6):1012- 5
X inactivation and dystrophin studies in a t(X;12) female: evidence for
biochemical normalization in Duchenne muscular dystrophy carriers.
Wenger SL, Steele MW, Hoffman EP, Barmada MA, Wessel HB.
Division of Medical Genetics, Children's Hospital of Pittsburgh, PA 15213- 2583.
A 4- year- old girl was identified with high creatine kinase (CK) values, and mild
muscle weakness in a limb- girdle distribution. Results of dystrophin analysis of
the muscle biopsy were consistent with a manifesting heterozygote for Duchenne
muscular dystrophy. In peripheral lymphocytes she had a t(X;12) (p21.2;q24.33).
Late DNA replication studies demonstrated inactivation of the normal X
chromosome in 99.4% of cells. Dystrophin immunofluorescence showed 64%
dystrophin- negative muscle fibers. Dystrophin content of muscle by immunoblot
was approximately 5% of normal. The discordance between the percent of normal X
inactivation and percent of dystrophin- negative cells may be explained by
compensatory protection of dystrophin by rare nuclei with the normal X active in
multi- nucleated muscle fibers with shared cytoplasm.
PMID: 1415326 [PubMed - indexed for MEDLINE]
35: J Inherit Metab Dis 1992;15(4):539- 50
Duchenne muscular dystrophy: gene and gene product; mechanism of mutation in the
gene.
Worton RG.
Department of Genetics and Research Institute, Hospital for Sick Children,
Toronto, Ontario, Canada.
The X- linked gene responsible for Duchenne muscular dystrophy encodes
dystrophin, a high- molecular- weight cytoskeletal protein. Studies in several
laboratories have revealed deletion of one or more exons in 60% of affected
boys; quantitative analysis in our laboratory has detected duplication of exons
in another 6%. The severe Duchenne phenotype is associated with deletions or
duplications that shift the reading frame of the message, whereas the milder
Becker muscular dystrophy is associated with deletions or duplications that
maintain the reading frame. Patients who have neither deletion nor duplication
may have nonsense mutations, one of which has been detected by predicting the
site of the mutation from the size of the truncated protein. Rare females with
the disease have a translocation that disrupts the dystrophin gene on one X
chromosome and causes non- random inactivation of the normal X, resulting in the
expression of the disease. The high frequency of new mutation provides an
opportunity to study the mechanism of chromosomal rearrangement that is
characteristic of the disease. Our laboratory has focused on the translocations
in females and on duplications in affected males. The X- autosome translocations
of affected females are all de novo events that originated in the paternal set
of chromosomes. Molecular characterization of the translocation junctions
revealed reciprocal translocation with both deletion and addition of nucleotides
at the junction, suggestive of a breakage and reunion mechanism. Duplications
studied to date are all tandem in nature and sequence analysis of duplication
junctions has revealed both homologous and non- homologous recombination. Marker
segregation analysis has revealed that five out of five duplications originated
in a single X chromosome of one of the maternal grandparents, suggesting that
the recombination event is unequal sister chromatid exchange.
Publication Types:
Review
Review, Tutorial
PMID: 1528015 [PubMed - indexed for MEDLINE]
36: Am J Med Genet 1991 Sep 1;40(3):354- 64
Discordance of muscular dystrophy in monozygotic female twins: evidence
supporting asymmetric splitting of the inner cell mass in a manifesting carrier
of Duchenne dystrophy.
Lupski JR, Garcia CA, Zoghbi HY, Hoffman EP, Fenwick RG.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
In 1990, Richards et al. reported dramatically skewed lyonization in a set of
female monozygotic twins heterozygous for Duchenne muscular dystrophy (DMD). The
skewed inactivation pattern was symmetrical in opposite directions, one twin
being affected with DMD, the other one being normal. Here, we report an
additional set of female monozygotic twins heterozygous for a mutation at the
dystrophin locus. Similarly, one shows a manifesting carrier phenotype while one
is normal. However, unlike the previous report, we find a skewed X inactivation
pattern only in the affected twin, while the normal twin showed a random X
inactivation pattern. Our results lend considerable experimental support for the
models of twinning and X inactivation recently outlined by Nance in 1990, in
that these twins probably represent asymmetric splitting of the inner cell mass
(ICM): The affected twin likely arose when a small proportion of the ICM split
off after lyonization had occurred. In this situation, the original ICM could
give rise to the normal twin with random lyonization, while the newly split
cells would experience catch- up growth and lead to the affected twin. Genetic
studies of this family showed that the specific dystrophin gene mutation was an
exon duplication that arose sporadically in the paternally derived X chromosome.
PMID: 1683155 [PubMed - indexed for MEDLINE]
37: Hum Hered 1991;41(6):370- 8
Estimate of the intrafamilial correlation for serum creatine kinase and pyruvate
kinase in females at risk for Duchenne and Becker muscular dystrophies.
Rabbi- Bortolini E, Dal Colletto GM, Passos- Bueno MR, Vainzof M, Rapaport D, Zatz
M.
Departamento de Genetica, Universidade Federal do Espirito Santo, Vitoria.
In order to verify the possibility of nonrandom X- inactivation in females
heterozygous for Duchenne (DMD) and Becker (BMD) muscular dystrophies,
intrafamilial correlations and the heritabilities for serum creatine kinase (CK)
and pyruvate kinase (PK) were estimated in a large sample of females belonging
to families with affected patients. The results of the present investigation
suggest that the apparent intrafamilial correlations for serum CK reported in
previous studies in DMD families are not related with the presence of the
DMD/BMD gene. Our data do not seem to support the hypothesis of a gene leading
to a preferential inactivation of the X- chromosome in females at risk for the
dystrophin gene.
PMID: 1797630 [PubMed - indexed for MEDLINE]
38: Am J Hum Genet 1990 Apr;46(4):672- 81
Skewed X inactivation in a female MZ twin results in Duchenne muscular
dystrophy.
Richards CS, Watkins SC, Hoffman EP, Schneider NR, Milsark IW, Katz KS, Cook JD,
Kunkel LM, Cortada JM.
GeneScreen, Department of Pediatrics, University of Texas Southwestern Medical
Center, Dallas 75207.
One of female MZ twins presented with muscular dystrophy. Physical examination,
creatine phosphokinase levels, and muscle biopsy were consistent with Duchenne
muscular dystrophy (DMD). However, because of her sex she was diagnosed as
having limb- girdle muscular dystrophy. With cDNA probes to the DMD gene, a gene
deletion was detected in the twins and their mother. The de novo mutation which
arose in the mother was shown by novel junction fragments generated by HindIII,
PstI, or TaqI when probed with cDNA8. Additional evidence of a large gene
deletion was given by novel SfiI junction fragments detected by probes p20,
J- Bir, and J- 66 on pulsed- field gel electrophoresis (PFGE). Immunoblot analysis
of muscle from the affected twin showed dystrophin of normal size but of reduced
amount. Immunofluorescent visualization of dystrophin revealed foci of
dystrophin- positive fibers adjacent to foci of dystrophin- negative fibers. These
data indicate that the affected twin is a manifesting carrier of an abnormal DMD
gene, her myopathy being a direct result of underexpression of dystrophin.
Cytogenetic analysis revealed normal karyotypes, eliminating the possibility of
a translocation affecting DMD gene function. Both linkage analysis and DNA
fingerprint analysis revealed that each twin has two different X chromosomes,
eliminating the possibility of uniparental disomy as a mechanism for DMD
expression. On the basis of methylation differences of the paternal and maternal
X chromosomes in these MZ twins, we propose uneven lyonization (X chromosome
inactivation) as the underlying mechanism for disease expression in the affected
female.
PMID: 2180286 [PubMed - indexed for MEDLINE]
39: Am J Hum Genet 1989 Jul;45(1):63- 72
Brother/sister pairs affected with early- onset, progressive muscular dystrophy:
molecular studies reveal etiologic heterogeneity.
Francke U, Darras BT, Hersh JH, Berg BO, Miller RG.
Department of Human Genetics, Yale University School of Medicine, New Haven, CT.
An autosomal recessive (AR) form of muscular dystrophy that clinically resembles
Duchenne/Becker types exists, but its frequency is unknown. We have studied
three unrelated affected brother/sister pairs and their families for deletions
and polymorphisms with the entire dystrophin cDNA and other DNA probes from the
Xp21 region to test for involvement of the DMD locus. In family 1 a large
intragenic deletion was found in the affected male. The affected sister was
heterozygous for this deletion, but the mother was not, implying germinal
mosaicism. In family 2, no deletion was detected in the affected male. RFLP
analysis revealed that the affected male and an unaffected sister shared a
complete Xp21 haplotype while the affected sister had inherited a recombinant
Xp21 region resulting from a crossover between pERT 87- 15 and J- Bir. Only the 5'
region of the dystrophin gene was shared with the affected boy. X- inactivation
studies using a polymorphism in the 5'- flanking region of the HPRT gene, in
conjunction with methylation- sensitive enzymes, revealed random X inactivation
in the affected girl's leukocytes. In a muscle biopsy from the affected male,
the dystrophin protein was present in normal amount and size. Family 3 was
informative for four RFLPs detected with dystrophin cDNA probes which span the
entire gene. The affected male was found to share the complete dystrophin RFLP
haplotype with his unaffected brother, while his affected sister had inherited
the other maternal haplotype. It is concluded that the clinical presentation of
early- onset, progressive muscular dystrophy in a male and in his karyotypically
normal sister can be caused by mutations at different loci. While in family 1 a
deletion in the dystrophin gene is responsible, this gene does not appear to be
involved in families 2 and 3.
PMID: 2568091 [PubMed - indexed for MEDLINE]
40: J Med Genet 1988 Jun;25(6):377- 82
Inherited deletion of subband Xp21.13 in a male with Duchenne muscular
dystrophy.
Werner W, Spiegler AW.
Abteilung Medizinische Genetik, Medizinische Akademie Erfurt, German Democratic
Republic.
The chromosomes of a male patient who suffers from Duchenne muscular dystrophy
(DMD) with a molecular deletion were examined with an improved high resolution R
type replication banding technique. High resolution cytogenetic analysis of the
proband revealed a deletion of the Xp21.13 subband. His healthy mother was
heterozygous for the deletion, which is subject to random X inactivation in
lymphocytes. The X chromosomes of the proband's grandmother were normal,
suggesting that the deletion of the Xp21.13 subband in the mother was a new
mutation. The finding of a very small, cytologically visible Xp21.1 deletion in
a male DMD patient with a molecular deletion emphasises the importance of
resolving the fine structure in the Xp21 region.
Publication Types:
Review
Review of Reported Cases
PMID: 3294410 [PubMed - indexed for MEDLINE]
41: J Med Genet 1988 Mar;25(3):213- 6
Anomalous X chromosome inactivation: the link between female zygotes,
monozygotic twinning, and neural tube defects?
Publication Types:
Letter
PMID: 3351914 [PubMed - indexed for MEDLINE]
42: J Neurol Sci 1987 Jul;79(3):337- 44
The clinical consequences of X- chromosome inactivation: Duchenne muscular
dystrophy in one of monozygotic twins.
Pena SD, Karpati G, Carpenter S, Fraser FC.
We have ascertained retrospectively a female patient, one of identical twins,
who was diagnosed at age 23 years as having Duchenne muscular dystrophy (DMD). A
muscle biopsy at that time showed a pattern in which large areas of destroyed
muscle fibers replaced with adipose tissue were interspersed with
normal- appearing muscle fascicles. The visualization of Barr bodies in the
muscle biopsy, plus the patient's normal menstrual history served to rule out
Turner's syndrome. The clinical expression of DMD in only one of monozygotic
twins is strongly suggestive of uneven lyonization, with an excess of paternally
derived X- chromosomes being inactivated in the patient. This view is supported
by the appearance of the muscle biopsy. Twinning may conceivably predispose to
uneven lyonization by reducing the size of the muscle cell anlage at the time of
X- chromosome inactivation. Alternatively, lyonization may occur before the
splitting of the embryonic mass, and by chance, the two embryonic centers could
end up with a significantly different proportion of active maternal and paternal
X- chromosomes.
PMID: 3612177 [PubMed - indexed for MEDLINE]
43: J Cell Sci 1987 Feb;87 ( Pt 1):163- 9
Spreading behaviour of cultured fibroblasts from carriers of Duchenne muscular
dystrophy.
Pizzey JA, Witkowski JA, Jones GE.
Department of Biophysics, Cell and Molecular Biology, King's College London, UK.
Cultured skin fibroblasts from patients with Duchenne muscular dystrophy (DMD)
are more sensitive than normal cells to prolonged exposure to the ionophore
monensin. In a cell spreading assay in which cells were preincubated with
monensin and subsequently allowed to adhere to and spread on a glass substratum
in serum- free medium for 100 min, the mean transformed cell area of normal and
DMD cells was 5.97 +/- 0.11 and 5.29 +/- 0.03, respectively. Cultured
fibroblasts from carriers of DMD yielded a value of 5.59 +/- 0.03, which is
intermediate between, and significantly different from, the values for both
normal and DMD cultures. This result would be predicted on the basis of random
X- chromosome inactivation in female carriers of this disorder. However,
comparison of DMD carrier cell spreading data with data obtained from pooled and
summated measurements taken from separate experiments using either normal or DMD
fibroblasts suggest a more complex situation. Examination of the variance of the
means of cell area for the true carrier population and the summated normal and
DMD population provides evidence suggesting that some form of cellular
interaction may occur between the two cell genotypes in culture.
PMID: 3667711 [PubMed - indexed for MEDLINE]
44: J Med Genet 1986 Dec;23(6):484- 90
Muscular dystrophy in girls with X;autosome translocations.
Boyd Y, Buckle V, Holt S, Munro E, Hunter D, Craig I.
Twenty known cases of X;autosome translocations with breakpoints at Xp21
associated with Duchenne or Becker muscular dystrophy in girls are reviewed. The
variable severity described for different persons may reflect differences in X
inactivation or in the nature of the genomic target disrupted. High resolution
cytogenetic studies on 12 cases indicate breakpoints on the X chromosome at
Xp21.1 or Xp21.2. Translocation chromosomes from several of these cases have
been isolated in human/mouse somatic cell hybrids. Molecular heterogeneity in
the breakpoint positions has been established by probing DNA from these hybrids
with a range of cloned sequences known to be located within, or closely linked
to, the Duchenne region. The minimum separation between the most distal and the
most proximal breakpoints is 176 kb suggesting that, if a single gene is
involved, it must be large. Alternatively, the translocations may affect
different genes, or confer alterations to regulatory sequences which operate at
a distance.
PMID: 3806636 [PubMed - indexed for MEDLINE]
45: J Med Genet 1986 Dec;23(6):494- 500
Duchenne muscular dystrophy in one of monozygotic twin girls.
Burn J, Povey S, Boyd Y, Munro EA, West L, Harper K, Thomas D.
Monozygotic twin girls are reported, one of whom has the typical clinical
features of Duchenne muscular dystrophy despite a normal female karyotype.
Although certain features of the biopsy were atypical, the clinical diagnosis
was supported by persistent markedly raised blood creatine kinase levels and
findings typical of DMD on electromyography and magnetic resonance spectroscopy.
Analysis of an X linked DNA polymorphism in 16 independent somatic cell hybrids
made between cells derived from each girl and a mouse line suggest that in one
twin only the maternal X chromosome is active, whereas in the other the active X
was paternally derived. More data are needed to exclude sampling error. These
preliminary experimental results support the hypothesis that both girls are
heterozygous for Duchenne muscular dystrophy. X inactivation, by chance,
resulted in two contrasting cell masses with different active X chromosomes.
This segregation was followed by, and may even have resulted in, twinning into a
female pair, one normal and one with the full clinical features of the disease.
PMID: 2879922 [PubMed - indexed for MEDLINE]
46: J Med Genet 1986 Apr;23(2):171- 3
Duchenne muscular dystrophy in a female with a translocation involving Xp21.
Nevin NC, Hughes AE, Calwell M, Lim JH.
A female with Duchenne muscular dystrophy, diagnosed at the age of 3 years 8
months, is reported. Chromosome studies revealed an X;autosome reciprocal
translocation t(X;5) (p21.2;q31.2). With the BrdU- Hoechst 33258- Giemsa
technique, there was nonrandom preferential inactivation of the normal X. Our
patient is the ninth reported case of Duchenne muscular dystrophy associated
with an X;autosome translocation. In all cases the breakpoint in the X
chromosome is in band p21 at or near the site of the DMD gene.
PMID: 3712394 [PubMed - indexed for MEDLINE]
47: Hum Genet 1984;67(1):115- 9
Expression of an X- linked muscular dystrophy in a female due to translocation
involving Xp21 and non- random inactivation of the normal X chromosome.
Verellen- Dumoulin C, Freund M, De Meyer R, Laterre C, Frederic J, Thompson MW,
Markovic VD, Worton RG.
A young female was diagnosed as having X- linked muscular dystrophy of the
Duchenne type. Chromosome studies, including trypsin- Giemsa banding, Quinacrine
fluorescence, and nucleolus organizer region (NOR) silver staining revealed an
X- autosome reciprocal translocation t(X;21) (p21;p12). Utilizing both [3H]
thymidine autoradiography and the BrdU- Hoechst 33258- Giemsa technique,
lymphocytes and fibroblasts were found to show a preferential inactivation of
the normal X suggesting the presence of a single mutant gene on the translocated
X. This patient is one of seven reported cases of an X- linked muscular dystrophy
associated with an X- autosome translocation. In all seven cases the exchange
point in the X chromosome is in band p21 at or near the site of the Duchenne
gene.
PMID: 6745920 [PubMed - indexed for MEDLINE]
48: J Neurol Sci 1981 Mar;49(3):455- 63
Manifesting carrier of x- linked Duchenne muscular dystrophy.
Meola G, Scarpini E, Silani V, Scarlato G.
The authors have investigated the uncommon occurrence of a boy affected with
Duchenne muscular dystrophy (DMD) whose mother showed myopathic features in the
clinical history, EMG, biochemical tests and muscle biopsy. This study suggests
that the patient's mother is a manifesting carrier of X- linked DMD with
clinical, neurophysiological, biochemical and histological findings of X- linked
DMD with an almost complete inactivation of the paternal X- chromosome
(lyonization).
PMID: 7217994 [PubMed - indexed for MEDLINE]
49: Hum Genet 1980;54(3):309- 13
Tandem duplication dup(X)(q13q22) in a male proband inherited from the mother
showing mosaicism of X- inactivation.
Steinbach P, Horstmann W, Scholz W.
An aberrant X chromosome containing extra material in the long arm was observed
in a psychomotoric retarded boy and his healthy, short- statured mother. The
proband showed generalized muscular hypotony, growth retardation, and somatic
anomalies including hypoplastic genitalia and cryptorchism. Chromosomal banding
techniques suggested a tandem duplication of the segment Xq13 leads to Xq22. In
the mother the vast majority of lymphocytes showed late replication of the
aberrant X chromosome. Some of her cells, however, contained an apparently
active aberrant X. Both the early- and late- replicating aberrant X exhibited
late replication patterns very similar to those described for normal X
chromosomes in lymphocytes. Asynchrony of DNA replication among the two segments
Xq13 leads to Xq22 in the dup(X) was never observed. We consider that the
clinical picture of the proband is caused by an excess of active X material.
PMID: 7399525 [PubMed - indexed for MEDLINE]
50: Neurology 1977 Jun;27(6):537- 41
Failure of inactivation of Duchenne dystrophy X- chromosome in one of female
identical twins.
Gomez MR, Engel AG, Dewald G, Peterson HA.
Duchenne muscular dystrophy manifested in one of girl twins. The twins were
monozygous on the basis of red cell and HL antigens and skin graft
compatibility. Karyotyping, including banding techniques, showed a normal number
of chromosomes and a normal configuration of the X- chromosome in both twins. The
twins were identical in appearance until symptoms of Duchenne dystrophy
developed in one at age 4 years. The maternal uncle had classic Duchenne
dystrophy; the mother and the nonmanifesting twin showed evidence of being
heterozygous for Duchenne dystrophy. The phenotypic difference in monozygous
twins is readily explained by lyonization of the X- chromosome after twinning has
occurred. The findings substantiate the existence of Duchenne dystrophy
manifesting in females with normal karyotypes.
PMID: 559260 [PubMed - indexed for MEDLINE]