title: Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.
abstract: We recently reported a severe deficiency in collagen type VI, resulting from recessive mutations of the COL6A2 gene, in patients with Ullrich congenital muscular dystrophy. Their parents, who are all carriers of one mutant allele, are unaffected, although heterozygous mutations in collagen VI caused Bethlem myopathy. Here we investigated the consequences of three COL6A2 mutations in fibroblasts from patients and their parents in two Ullrich families. All three mutations lead to nonsense-mediated mRNA decay. However, very low levels of undegraded mutant mRNA remained in patient B with compound heterozygous mutations at the distal part of the triple-helical domain, resulting in deposition of abnormal microfibrils that cannot form extensive networks. This observation suggests that the C-terminal globular domain is not essential for triple-helix formation but is critical for microfibrillar assembly. In all parents, the COL6A2 mRNA levels are reduced to 57-73% of the control, but long term collagen VI matrix depositions are comparable with that of the control. The almost complete absence of abnormal protein and near-normal accumulation of microfibrils in the parents may account for their lack of myopathic symptoms.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Rui-Zhu
authors.initials: RZ
authors.lastname: Zhang
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Te-Cheng
authors.initials: TC
authors.lastname: Pan
authors.forename: Stefano
authors.initials: S
authors.lastname: Squarzoni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Guglielmina
authors.initials: G
authors.lastname: Pepe
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000737:chemistry* / Q000378:metabolism*; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D005192:Family Health; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D024142:Collagen Type VI; D012333:RNA, Messenger