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Pan TC, Zhang RZ, Sudano DG, et al. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet. 2003;73(2):355-69doi: 10.1086/377107.
Pan, T. C., Zhang, R. Z., Sudano, D. G., Marie, S. K., Bönnemann, C. G., & Chu, M. L. (2003). New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. American journal of human genetics, 73(2), 355-69. https://doi.org/10.1086/377107
Pan, Te-Cheng, et al. "New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype." American journal of human genetics vol. 73,2 (2003): 355-69. doi: https://doi.org/10.1086/377107
Pan TC, Zhang RZ, Sudano DG, Marie SK, Bönnemann CG, Chu ML. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet. 2003 Aug;73(2):355-69. doi: 10.1086/377107. Epub 2003 Jul 01. PMID: 12840783; PMCID: PMC1180372.
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Am J Hum Genet. 2003 Aug;73(2):355-69. doi: 10.1086/377107. Epub 2003 Jul 01.

New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.

American journal of human genetics

Te-Cheng Pan, Rui-Zhu Zhang, Dominick G Sudano, Suely K Marie, Carsten G Bönnemann, Mon-Li Chu

Affiliations

  1. Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.

PMID: 12840783 PMCID: PMC1180372 DOI: 10.1086/377107

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.

References

  1. Eur J Paediatr Neurol. 2002;6(4):193-8 - PubMed
  2. Neurology. 2002 Sep 24;59(6):920-3 - PubMed
  3. Lancet. 2002 Nov 2;360(9343):1419-21 - PubMed
  4. J Biol Chem. 2002 Nov 15;277(46):43557-64 - PubMed
  5. Brain. 1976 Mar;99(1):91-100 - PubMed
  6. J Biol Chem. 1988 Dec 15;263(35):18601-6 - PubMed
  7. J Neurol. 1989 Feb;236(2):108-10 - PubMed
  8. EMBO J. 1989 Jul;8(7):1939-46 - PubMed
  9. EMBO J. 1990 Feb;9(2):385-93 - PubMed
  10. J Biol Chem. 1990 Sep 15;265(26):15349-52 - PubMed
  11. Annu Rev Biophys Biophys Chem. 1991;20:137-52 - PubMed
  12. EMBO J. 1992 Dec;11(12):4281-90 - PubMed
  13. Eur J Biochem. 1994 Apr 1;221(1):177-85 - PubMed
  14. Nat Genet. 1995 Mar;9(3):293-8 - PubMed
  15. Nucleic Acids Res. 1995 Jun 11;23(11):1854-61 - PubMed
  16. Genomics. 1995 Oct 10;29(3):801-3 - PubMed
  17. Nat Genet. 1996 Sep;14(1):113-5 - PubMed
  18. J Biol Chem. 1997 Oct 17;272(42):26522-9 - PubMed
  19. J Biol Chem. 1998 Feb 20;273(8):4761-8 - PubMed
  20. J Biol Chem. 1998 Mar 27;273(13):7423-30 - PubMed
  21. Brain Dev. 1998 Mar;20(2):65-74 - PubMed
  22. Hum Mol Genet. 1998 May;7(5):807-12 - PubMed
  23. Brain. 1999 Apr;122 ( Pt 4):649-55 - PubMed
  24. Biochem Biophys Res Commun. 1999 May 19;258(3):802-7 - PubMed
  25. J Biol Chem. 1999 Jul 30;274(31):21817-22 - PubMed
  26. Genome Res. 2000 Jul;10(7):899-907 - PubMed
  27. Nat Genet. 2000 Sep;26(1):51-5 - PubMed
  28. Ann Med. 2001 Feb;33(1):7-21 - PubMed
  29. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7516-21 - PubMed
  30. Ann Neurol. 2001 Aug;50(2):261-5 - PubMed
  31. Curr Opin Neurol. 2001 Oct;14(5):575-82 - PubMed
  32. J Biol Chem. 2002 Jan 18;277(3):1949-56 - PubMed
  33. Neuropediatrics. 1981 Aug;12(3):197-208 - PubMed
  34. J Biol Chem. 1981 Dec 25;256(24):13193-9 - PubMed
  35. Biochem J. 1983 May 1;211(2):303-11 - PubMed
  36. Am J Hum Genet. 1988 Mar;42(3):435-45 - PubMed
  37. Neurology. 2002 Feb 26;58(4):593-602 - PubMed
  38. Muscle Nerve. 2002 Apr;25(4):513-9 - PubMed
  39. Am J Hum Genet. 2002 Jun;70(6):1446-58 - PubMed
  40. Neuromuscul Disord. 2002 Nov;12(9):889-96 - PubMed

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