Frameshift mutation in the collagen VI gene causes Ullrich's disease

Higuchi, Itsuro; Shiraishi, Tadafumi; Hashiguchi, Teruto; Suehara, Masahito; Niiyama, Takahito; Nakagawa, Masanori; Arimura, Kimiyoshi; Maruyama, Ikuro; Osame, Mitsuhiro

doi:10.1002/ana.1120

Cited by 98 publications

(71 citation statements)

References 19 publications

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“…The electrostatic potential values for the C2 region encompassing the Arg-876 site ranged from (ϩ)92.6 to (ϩ)132.6, whereas the values for the area surrounding the Ser-876 mutation site ranged from (ϩ)17.1 to (ϩ)68. 4.…”

Section: Two Patients With Homozygous Missense Mutations In Col6a2-mentioning

confidence: 99%

Recessive COL6A2 C-globular Missense Mutations in Ullrich Congenital Muscular Dystrophy

Zhang¹,

Zou

Pan³

et al. 2010

Journal of Biological Chemistry

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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 collagen VI molecules. The minute amount of collagen VI secreted by the R876S fibroblasts was solely composed of a faster migrating chain corresponding to the C2a splice variant with an alternative C2 subdomain. In transfected cells, the C2a splice variant was able to assemble into short microfibrils. Together, the results suggest that the C2a splice variant may functionally compensate for the loss of the normal COL6A2 chain when mutations occur in the C2 subdomain.Ullrich congenital muscular dystrophy (UCMD, 2 OMIM 254090) has recently emerged as one of the most prevalent forms of congenital muscular dystrophy (1, 2). The disorder is characterized by severe muscle weakness in conjunction with proximal joint contractures and co-existing distal joint hypermobility (3). Children afflicted with UCMD may never achieve independent ambulation or may be able to walk for only a limited period of time. They may suffer from respiratory insufficiency, leading to early demise if not treated. UCMD was initially thought to be a recessive condition caused by mutations in the COL6A1, COL6A2, or COL6A3 genes encoding three collagen VI chains (4 -6). We have demonstrated that the disease can also result from a dominant mutation in COL6A1 (7). It is now apparent that dominant mutations in the three collagen VI genes are common in UCMD patients (8, 9).Collagen VI is a ubiquitously expressed extracellular matrix protein composed of ␣1(VI), ␣2(VI), and ␣3(VI) chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively (10). Each chain is made up of a triple-helical domain flanked by N-and C-globular regions that consist mainly of von Willebrand factor, type A (vWF-A) modules (11,12) (Fig. 1A). There are two vWF-A modules in the C-globular region of each chain, named C1 and C2 subdomains, where C2 is m...

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Section: Two Patients With Homozygous Missense Mutations In Col6a2-mentioning

confidence: 99%

Recessive COL6A2 C-globular Missense Mutations in Ullrich Congenital Muscular Dystrophy

Zhang¹,

Zou

Pan³

et al. 2010

Journal of Biological Chemistry

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“…In 2001, UCMD was first shown to result from a deficiency in collagen VI due to recessive mutations in COL6A2, one of the three subunit genes encoding the protein (Camacho Vanegas et al 2001;Higuchi et al 2001). Since then, mutations in all three collagen VI genes have been reported in nine families, eight of which carry homozygous or compound heterozygous frameshift, nonsense, or splice junction mutations in COL6A2 or COL6A3 that result in the absence or severe reduction of collagen VI protein (Demir et al 2002;Ishikawa et al 2002).…”

Section: Introductionmentioning

confidence: 99%

A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy

et al. 2005

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Ullrich congenital muscular dystrophy (UCMD) is a severe disorder caused, in most cases, by a deficiency in collagen VI microfibrils. Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have been identified in eight of the nine UCMD patients reported thus far. A heterozygous COL6A1 gene deletion, resulting in a mutant protein that exerts a dominant negative effect, has recently been described in a severely affected UCMD patient. Here we describe a patient in whom reverse transcription-PCR analysis of fibroblast RNA suggested a heterozygous in-frame deletion of exon 13 in the triple-helical domain of COL6A2, which is predicted to be dominantly acting. However, a homozygous A fi G mutation at À10 of intron 12 was found in the genomic DNA. The intron mutation activated numerous cryptic splice acceptor sites, generating normal and exon 13-deleted COL6A2 mRNA, and multiple aberrant transcripts containing frameshifts that were degraded through a nonsense-mediated decay mechanism. Northern analysis indicated diminished COL6A2 mRNA expression as the primary pathogenic mechanism in this UCMD patient. Our results underscore the importance of multifaceted analyses in the accurate molecular diagnosis and interpretation of genotype-phenotype correlations of UCMD.

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“…The mutant cells failed to assemble triple-helical collagen VI due to the defect in COL6A2 protein. Because type VI collagen is one of the important ECM components maintaining the structural integrity of skeletal muscle, a defect in collagen VI results in dystrophic muscle changes (15,16). NMD inhibition caused upregulation of PTC-containing COL6A2 mRNA and protein, resulting in the assembly of triple-helical collagen VI and partial rescue of the mutant phenotype (Fig.…”

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confidence: 99%

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

Usuki

Yamashita

Shiraishi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI α 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cellcycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases.therapy | genetic disorder with premature termination codon | siRNA

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Frameshift mutation in the collagen VI gene causes Ullrich's disease

Cited by 98 publications

References 19 publications

Recessive COL6A2 C-globular Missense Mutations in Ullrich Congenital Muscular Dystrophy

Recessive COL6A2 C-globular Missense Mutations in Ullrich Congenital Muscular Dystrophy

A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

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