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COL5A1 Signal Peptide Mutations Interfere with Protein Secretion and Cause Classic Ehlers-Danlos Syndrome
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| Abstract |
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| Classic Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disease characterized by skin hyperextensibility, atrophic scarring, joint hypermobility and generalized tissue fragility. Mutations in COL5A1 and COL5A2, encoding the type V collagen pro alpha 1- and pro alpha 2-chain, are found in similar to 50% of patients with classic EDS. The majority of mutations lead to a non-functional COL5A1 allele, as a result of the introduction of a premature stopcodon in one COL5A1 transcript. A minority of mutations affect the structure of the type V collagen central helical domain. We show that mutations in the signal peptide (SP) domain of the prepro alpha 1(V)-collagen chain cause classic EDS. The missense mutations (p.L25R and p.L25P) are located in the crucial hydrophobic SP core, which is indispensible for preprotein translocation into the endoplasmic reticulum. As a result, mutant type V procollagen is retained within the cell, leading to a decreased amount of type V collagen in the extracellular matrix and disturbed collagen fibrillogenesis. Our findings further support the observation that decreased availability of type V (pro) collagen is a key factor and a shared mechanism in the pathogenesis of classic EDS. (C) 2008 Wiley-Liss, Inc. |
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English
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Human mutation. - New York, N.Y. | |
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New York, N.Y. : 2009
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1059-7794
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30:2(2009), p. E395-E403
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000279979200008
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