COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome.
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.
Symoens
Sofie
S
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Malfait
Fransiska
F
Renard
Marjolijn
M
André
Josette
J
Hausser
Ingrid
I
Loeys
Bart
B
Coucke
Paul
P
De Paepe
Anne
A
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*
C530725:COL5A1 protein, human; D024062:Collagen Type V; D024022:Fibrillar Collagens; D050505:Mutant Proteins; D021382:Protein Sorting Signals