Mosaic Expression of Dystrophin in Symptomatic Carriers of Duchenne's Muscular Dystrophy

Arahata, Kiichi; Ishihara, Tadayuki; Kamakura, Keiko; Tsukahara, Toshifumi; Ishiura, Shoichi; Baba, Chikako; Matsumoto, Tadashi; Nonaka, Ikuya; Sugita, Hideo

doi:10.1056/nejm198901193200302

Cited by 134 publications

(38 citation statements)

References 17 publications

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“…18) Dystrophin labeling of muscle biopsies from manifesting carriers shows a mosaic pattern, with reduced or absent dystrophin. 33,34) Immunohistochemistry findings are concordant with western blot analysis for dystrophin. 34) No association is seen between the pattern of distribution of dystrophin and clinical severity of manifesting carriers.…”

Section: Insights Of Diagnostic Strategies Of Female Carrier Of Dmd: supporting

confidence: 56%

Female Carriers of Duchenne Muscular Dystrophy

Cho

Choi

2013

J Genet Med

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males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers.1, 2, 4) Therefore, here we reviewed recent studies to meet the need for a better understanding about the characterization of female carriers of DMD. What is dystrophinopathies?Duchenne's description of DMD was published in 1861. He referred to the disease as "hypertrophic paraplegia of infancy due to a cerebral cause". IntroductionDuchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy. The milder form of this disease is called Becker muscular dystrophy(BMD).1) The disorder is also called dystrophinopathy because it caused by mutations in the DMD gene, which encodes dystrophin, on Xp21.2) Most heterozygous female carriers of DMD are subclinical. Therefore, identification of dystrophinopathy carriers may be only con sidered on clinical grounds such as clear X-linked family history of muscular dystrophy. However, myopathic muscle biopsy and advanced molecular diagnostic analysis can be used to identify the carrier state of DMD without a positive family history of dystrophinopathy , which is present in 10% of women with hyperCKemia.3) In addition, two-thirds of mothers of affected www.e-kjgm.org Dystrophinopathy, caused by mutations in the DMD gene, presents with variable clinical phenotypes ranging from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy(BMD) forms. DMD is a recessive X-linked form of muscular dystrophy. Two-thirds of mothers of affected males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers. The symptoms of female carriers of DMD range from mild muscle weakness to severe gait problems. The most commonly presented symptom is mild proximal muscle weakness, which is often asymmetric and progressive, but shows variable clinical spectrum with BMD of more severe DMD-like phenotype. Atypical presentations in manifesting carriers are myalgia or cramps without limb weakness, isolated cardiomyopathy and camptocormia. Multiplex PCR and MLPA analysis are common techniques to identify mutations in the DMD gene. Relationship between X-chromosome inactivation and clinical severity is not clear. Female carriers of DMD are not less common, and they have an important role of birth of a male DMD.

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Section: Insights Of Diagnostic Strategies Of Female Carrier Of Dmd: supporting

confidence: 56%

Female Carriers of Duchenne Muscular Dystrophy

Cho

Choi

2013

J Genet Med

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“…2,5). These include analysis of protein polymorphisms to distinguish Xa and Xi expression (6), detection of mosaic expression of a protein in tissues of heterozygous carriers of X-linked disorders (7)(8)(9), or comparison of protein or transcript levels among individuals with different numbers of X chromosomes (10)(11)(12)(13).…”

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A first-generation X-inactivation profile of the human X chromosome

Carrel

Cottle

Goglin

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

347

246

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In females, most genes on the X chromosome are generally assumed to be transcriptionally silenced on the inactive X as a result of X inactivation. However, particularly in humans, an increasing number of genes are known to ''escape'' X inactivation and are expressed from both the active (Xa) and inactive (Xi) X chromosomes; such genes reflect different molecular and epigenetic responses to X inactivation and are candidates for phenotypes associated with X aneuploidy. To identify genes that escape X inactivation and to generate a first-generation X-inactivation profile of the X, we have evaluated the expression of 224 X-linked genes and expressed sequence tags by reverse-transcription-PCR analysis of a panel of multiple independent mouse͞human somatic cell hybrids containing a normal human Xi but no Xa. The resulting survey yields an initial X-inactivation profile that is estimated to represent Ϸ10% of all X-linked transcripts. Of the 224 transcripts tested here, 34 (three of which are pseudoautosomal) were expressed in as many as nine Xi hybrids and thus appear to escape inactivation. The genes that escape inactivation are distributed nonrandomly along the X; 31 of 34 such transcripts map to Xp, implying that the two arms of the X are epigenetically and͞or evolutionarily distinct and suggesting that genetic imbalance of Xp may be more severe clinically than imbalance of Xq. A complete X-inactivation profile will provide information relevant to clinical genetics and genetic counseling and should yield insight into the genomic and epigenetic organization of the X chromosome.

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“…Immunofluorescence studies of dystrophin localization in Becker dystrophy patients have found a disease-specific "patchy" immunofluorescent pattern (7,8). Though (12,13).…”

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confidence: 99%

“…Becker Moreover, dystrophin deficiency has been shown to be specific for Duchenne muscular dystrophy by both techniques (10,12) (Figs. 1 and 5).…”

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confidence: 99%

Dystrophin diagnosis: comparison of dystrophin abnormalities by immunofluorescence and immunoblot analyses.

Arahata

Hoffman

Kunkel

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

116

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Immunoblot characterization and immunofluorescence localization of dystrophin are presented for 76 human patients with various neuromuscular diseases. Normal dystrophin (shown by immunoblotting) was invariably visualized as a continuous, peripheral membrane immunostaining of myofibers. Biochemical abnormalities of dystrophin (either lower or higher molecular weight dystrophin) resulted in patchy, discontinuous immunostaining, suggesting that the abnormal dystrophin proteins are not capable of creating a complete membrane cytoskeleton network. There was a very strong correlation of clinical diagnoses with the type of dystrophin abnormality; all Duchenne muscular dystrophy patient muscle contained no detectable dystrophin, Becker muscular dystrophy patient muscle had clearly abnormal dystrophin, and unrelated diseases showed normal dystrophin. However, a single patient of five carrying the diagnosis of Fukuyama dystrophy showed no detectable dystrophin and thus appeared to be a Duchenne dystrophy patient by the biochemical assays. We know of no other case of a patient with a disease thought to be unrelated to Duchenne/Becker dystrophy yet demonstrating dystrophin deficiency. Based on the data presented, we conclude that immunofluorescence is the best technique for the detection of female carriers of Duchenne dystrophy, whereas immunoblotting appears superior for the prognostic diagnosis of Becker muscular dystrophy.

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Mosaic Expression of Dystrophin in Symptomatic Carriers of Duchenne's Muscular Dystrophy

Cited by 134 publications

References 17 publications

Female Carriers of Duchenne Muscular Dystrophy

Female Carriers of Duchenne Muscular Dystrophy

A first-generation X-inactivation profile of the human X chromosome

Dystrophin diagnosis: comparison of dystrophin abnormalities by immunofluorescence and immunoblot analyses.

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