Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy

Carolyn (Sue) Richards, S. C. Watkins, E. P. Hoffman, N. R. Schneider, I. W. Milsark, K. S. Katz, J. D. Cook, L. M. Kunkel, J. M. Cortada

Research output: Contribution to journalArticle

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Abstract

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, PsrI, 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.

Original languageEnglish (US)
Pages (from-to)672-681
Number of pages10
JournalAmerican Journal of Human Genetics
Volume46
Issue number4
StatePublished - Apr 1990
Externally publishedYes

Fingerprint

X Chromosome Inactivation
Dystrophin
Duchenne Muscular Dystrophy
Gene Deletion
X Chromosome
Limb-Girdle Muscular Dystrophies
Uniparental Disomy
Genes
Muscles
DNA Fingerprinting
Muscular Dystrophies
Cytogenetic Analysis
Pulsed Field Gel Electrophoresis
Muscular Diseases
Creatine Kinase
Karyotype
Methylation
Physical Examination
Complementary DNA
Mothers

ASJC Scopus subject areas

  • Genetics

Cite this

Richards, C. S., Watkins, S. C., Hoffman, E. P., Schneider, N. R., Milsark, I. W., Katz, K. S., ... Cortada, J. M. (1990). Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy. American Journal of Human Genetics, 46(4), 672-681.

Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy. / Richards, Carolyn (Sue); Watkins, S. C.; Hoffman, E. P.; Schneider, N. R.; Milsark, I. W.; Katz, K. S.; Cook, J. D.; Kunkel, L. M.; Cortada, J. M.

In: American Journal of Human Genetics, Vol. 46, No. 4, 04.1990, p. 672-681.

Research output: Contribution to journalArticle

Richards, CS, Watkins, SC, Hoffman, EP, Schneider, NR, Milsark, IW, Katz, KS, Cook, JD, Kunkel, LM & Cortada, JM 1990, 'Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy', American Journal of Human Genetics, vol. 46, no. 4, pp. 672-681.
Richards CS, Watkins SC, Hoffman EP, Schneider NR, Milsark IW, Katz KS et al. Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy. American Journal of Human Genetics. 1990 Apr;46(4):672-681.
Richards, Carolyn (Sue) ; Watkins, S. C. ; Hoffman, E. P. ; Schneider, N. R. ; Milsark, I. W. ; Katz, K. S. ; Cook, J. D. ; Kunkel, L. M. ; Cortada, J. M. / Skewed X inactivation in a female MZ twin Results in duchenne muscular dystrophy. In: American Journal of Human Genetics. 1990 ; Vol. 46, No. 4. pp. 672-681.
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