• Citer

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

par Symoens, Sofie;Malfait, Fransiska;Renard, Marjolijn;André, Josette ;Hausser, Ingrid;Loeys, Bart;Coucke, Paul;De Paepe, Anne
Référence Human mutation, 30, 2, page (E395-E403)
Publication Publié, 2009-02

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

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.