Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.

The Journal of Biological Chemistry
Rui-Zhu ZhangMon-Li Chu

Abstract

Ullrich congenital muscular dystrophy (UCMD) is a disabling and life-threatening disorder resulting from either recessive or dominant mutations in genes encoding collagen VI. Although the majority of the recessive UCMD cases have frameshift or nonsense mutations in COL6A1, COL6A2, or COL6A3, recessive structural mutations in the COL6A2 C-globular region are emerging also. However, the underlying molecular mechanisms have remained elusive. Here we identified a homozygous COL6A2 E624K mutation (C1 subdomain) and a homozygous COL6A2 R876S mutation (C2 subdomain) in two UCMD patients. The consequences of the mutations were investigated using fibroblasts from patients and cells stably transfected with the mutant constructs. In contrast to expectations based on the clinical severity of these two patients, secretion and assembly of collagen VI were moderately affected by the E624K mutation but severely impaired by the R876S substitution. The E624K substitution altered the electrostatic potential of the region surrounding the metal ion-dependent adhesion site, resulting in a collagen VI network containing thick fibrils and spots with densely packed microfibrils. The R876S mutation prevented the chain from assembling into triple-helical...Continue Reading

References

Jun 5, 1982·Journal of Molecular Biology·J Warwicker, H C Watson
Oct 24, 1995·Proceedings of the National Academy of Sciences of the United States of America·A Qu, D J Leahy
Apr 1, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·T SasakiM L Chu
Jun 21, 2001·Proceedings of the National Academy of Sciences of the United States of America·O Camacho VanegasG Pepe
Aug 17, 2001·Annals of Neurology·I HiguchiM Osame
May 7, 2002·American Journal of Human Genetics·Ercan DemirPascale Guicheney
Sep 18, 2002·Immunological Reviews·Junichi Takagi, Timothy A Springer
Dec 11, 2002·The Journal of Biological Chemistry·Stephen BallAdrian Shuttleworth
Jan 30, 2003·Proceedings of the National Academy of Sciences of the United States of America·Thomas Vorup-JensenTimothy A Springer
Sep 8, 2004·Neuromuscular Disorders : NMD·Francesco Muntoni, Thomas Voit
Nov 26, 2004·Human Molecular Genetics·Naomi L BakerShireen R Lamandé
Sep 1, 2005·Annals of Neurology·Betti GiustiGuglielmina Pepe
Sep 6, 2005·Journal of Medical Genetics·A K Lampe, K M D Bushby
Sep 20, 2005·Molecular and Cellular Neurosciences·Stefania PetriniEnrico Bertini
Aug 22, 2006·Proceedings of the National Academy of Sciences of the United States of America·JianFeng ChenTimothy A Springer
Sep 22, 2007·Annals of Neurology·Naomi L BakerShireen R Lamandé
Dec 28, 2007·Neurology·R A PeatK N North
Feb 16, 2008·The Journal of Biological Chemistry·Sudheer Kumar GaraRaimund Wagener
Apr 11, 2008·The Journal of Biological Chemistry·Jamie FitzgeraldUwe Hansen
Oct 1, 2008·Annals of Neurology·Rishika A PaceShireen R Lamandé

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Citations

Jun 22, 2011·Nature Reviews. Neurology·Carsten G Bönnemann
Sep 29, 2011·Skeletal Muscle·Valérie AllamandGisèle Bonne
Mar 4, 2014·Neuromuscular Disorders : NMD·Carsten G BönnemannUNKNOWN Members of International Standard of Care Committee for Congenital Muscular Dystrophies
Feb 16, 2019·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Shireen R Lamandé, John F Bateman
Jul 29, 2020·The Journal of Biological Chemistry·Herimela Solomon-DegefaRaimund Wagener
Mar 22, 2015·The Journal of Biological Chemistry·Patrizia SabatelliLuciano Merlini
Nov 7, 2018·Pediatric Research·Carla Gabriela AsteggianoRaquel Dodelson de Kremer
May 18, 2021·Nature Reviews. Materials·Benjamin J BielajewKyriacos A Athanasiou
Jun 26, 2021·Orphanet Journal of Rare Diseases·Michio InoueSatoru Noguchi

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