Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the XXXX gene.

@entity1 @entity15354 @entity1414 @entity72140 @entity72141 @entity4173 @entity13239 @entity4243 @entity397 @entity6926 @entity72142 @entity1413 @entity72143
UNASSIGNED: @entity4243 ( @entity4243 ) is a heritable disorder of connective tissue caused by pathological variants in the @entity1414 gene, which encodes the a1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. @entity1413 manifests as an increased risk of @entity397 , perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of @entity1414 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen @entity1414 variants have previously been reported in these exons, of which four were associated with a severe @entity4243 phenotype. We identified two novel C-propeptide missense variants; @entity72140 , @entity72141 , and a non-stop mutation, @entity72142 , p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile @entity15354 . A previously reported variant @entity72143 is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for @entity1 with missense variants in the C-propeptide domain for other @entity1 collagen disorders including @entity13239 and @entity4173 ( @entity6926 ).    2015 Wiley Periodicals, Inc.
