title: 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.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.forename: Josette
authors.initials: J
authors.lastname: André
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D024062:Collagen Type V / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D005260:Female; D024022:Fibrillar Collagens / Q000648:ultrastructure; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D021382:Protein Sorting Signals / Q000235:genetics*
chemical_list: C530725:COL5A1 protein, human; D024062:Collagen Type V; D024022:Fibrillar Collagens; D050505:Mutant Proteins; D021382:Protein Sorting Signals