Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females

Journal Article · Wed Jun 01 04:00:00 EDT 1994 · American Journal of Human Genetics; (United States)

OSTI ID:7199979

Pegoraro, E; Wessel, H B; Schwartz, L; Hoffman, E P ^[1]; Schimke, R N ^[2]; Arahata, Kiichi; Hayashi, Yukiko ^[3]; Stern, H ^[4]; Marks, H ^[5]; Glasberg, M R ^[6]

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1. Univ. of Pittsburgh, PA (United States)
2. Kansas Univ. Medical Center, Kansas City (United States)
3. National Institute of Neurosciences, Tokyo (Japan)
4. Children's National Medical Center, Washington, DC (United States)
5. A.I. duPont Institute, Wilmington (United States)
6. Henry Ford Hospital, Detroit, MI (United States); and others

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 carries 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 the authors 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. They show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in the 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, the results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. The 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. 58 refs., 7 figs., 2 tabs.

• OSTI ID: 7199979
• Journal Information: American Journal of Human Genetics; (United States), Journal Name: American Journal of Human Genetics; (United States) Vol. 54:6; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

550400* -- Genetics
59 BASIC BIOLOGICAL SCIENCES
CHROMOSOMES
DETECTION
DISEASES
GENE MUTATIONS
HEREDITARY DISEASES
HETEROCHROMOSOMES
HUMAN CHROMOSOMES
HUMAN X CHROMOSOME
INACTIVATION
MUSCLES
MUTATIONS
X CHROMOSOME