COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome.

Abstract

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 proalpha1- and proalpha2-chain, are found in approximately 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 preproá1(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.

• Authors: Sofie Symoens, Fransiska Malfait, Marjolijn Renard, Josette André, Ingrid Hausser, Bart Loeys, Paul Coucke, Anne De Paepe
• Journal: Human mutation (Hum Mutat) Vol. 30 Issue 2 Pg. E395-403 (Feb 2009) ISSN: 1098-1004 [Electronic] United States
• PMID: 18972565 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• COL5A1 protein, human
• Collagen Type V
• Fibrillar Collagens
• Mutant Proteins
• Protein Sorting Signals

Topics

• Adult
• Amino Acid Sequence
• Base Sequence
• Cell Line
• Child
• Child, Preschool
• Collagen Type V (chemistry, genetics, metabolism)
• DNA Mutational Analysis
• Ehlers-Danlos Syndrome (genetics)
• Female
• Fibrillar Collagens (ultrastructure)
• Heterozygote
• Humans
• Immunoblotting
• Infant
• Infant, Newborn
• Male
• Molecular Sequence Data
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Plasmids (genetics)
• Protein Sorting Signals (genetics)