Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.
1992
A large kindred with adult-type X-linked
Alport syndromewas studied with regard to a defect in the recently described COL4A5 collagen gene.
Southern blotanalysis with COL4A5 cDNA probes showed loss of a MspI
restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of
type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y
repeat sequence, is
interrupted22 times by noncollagenous sequences. The mutation creates an additional
interruptionin the Gly-X-Y repeat motif, between
interruptions4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of
osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the
triple-helixformation, and, in turn, modifies the ultrastructural and functional characteristics of the
type IV collagennetwork inside the
glomerular basement membrane.
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