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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Pan, Te-Cheng Zhang, Rui-Zhu Marie, Suely K. Sudano, Dominick G. Bönnemann, Carsten G. Chu, Mon-Li |
| Description | Country affiliation: United States Author Affiliation: Pan TC ( Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.) |
| Abstract | Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33-amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations. |
| ISSN | 00029297 |
| e-ISSN | 15376605 |
| Journal | The American Journal of Human Genetics |
| Issue Number | 2 |
| Volume Number | 73 |
| Language | English |
| Publisher | Cell Press (on behalf of American Society of Human Genetics) |
| Publisher Date | 2003-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Collagen Type Vi Genetics Muscular Dystrophies Congenital Amino Acid Sequence Chemistry Dna, Complementary Dimerization Exons Extracellular Matrix Fibroblasts Genes, Dominant Genotype Heterozygote Introns Molecular Sequence Data Muscles Metabolism Pathology Phenotype Protein Structure, Tertiary Rna, Messenger Sequence Deletion Sequence Homology, Nucleic Acid Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, P.h.s. Discipline Human Genetics |
| Content Type | Text |
| Resource Type | Article Case study |
| Subject | Genetics Genetics (clinical) |
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