Compound heterozygosity for a disease-causing G148...[Am J Med Genet. 2000]

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1: Am J Med Genet. 2000 Jan 3;90(1):72-9. Links

Erratum in:: Am J Med Genet. 2000 Aug 14;93(4):342.

Compound heterozygosity for a disease-causing G1489E [correction of G1489D] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos syndrome: an explanation of intrafamilial variability?

Giunta C, Steinmann B.

Division of Metabolic and Molecular Diseases, Zürich University Children's Hospital, Zürich, Switzerland.

The classical type of Ehlers-Danlos syndrome (EDS) is an autosomal dominant connective tissue disorder characterized by skin hyperelasticity, tissue fragility, and joint hypermobility. We investigated the molecular defect of EDS in a three-generation family. Cultured dermal fibroblasts from the propositus and his daughter produced abnormal alpha1(V) and alpha2(V) collagen molecules. Mutation analysis by means of RNase cleavage and direct sequencing of reverse transcription-polymerase chain reaction products showed in both the presence of a heterozygous G1489E [correction] mutation in the COL5A1 gene, which represents the first report of a glycine substitution in the main triple-helical region of alpha1(V) collagen. In the propositus, his unaffected daughter, and mother we identified a further newly recognized G530S substitution in the NH2-terminal domain, which did not cosegregate with the EDS phenotype and was found in only one of 51 unrelated control individuals. Because the NH2-terminal domain plays a crucial role in modulating fibril formation, the G530S substitution may alter the structure and function of this region and consequently the formation of collagen fibrils. Indeed, indirect evidence supports our hypothesis: (1) the EDS phenotype in the compound heterozygous propositus is more severe than that of his affected daughter with the G1489E [correction] mutation only; (2) his unaffected daughter and mother with the G530S substitution present with thin skin and delayed wound healing; (3) as does the only control individual with the same substitution. Thus, in the compound heterozygous propositus the EDS phenotype is caused by the G1489E [correction] mutation and possibly aggravated by the G530S substitution, which may explain intrafamilial variability.

PMID: 10602121 [PubMed - indexed for MEDLINE]

Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. [Am J Med Genet. 2002]
COL5A1 exon 14 splice acceptor mutation causes a functional null allele, haploinsufficiency of alpha 1(V) and abnormal heterotypic interstitial fibrils in Ehlers-Danlos syndrome II. [J Biol Chem. 2001]
A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers-Danlos syndrome type II in two British families. [Am J Hum Genet. 1998]
COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. [Am J Hum Genet. 2000]
Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I. [Hum Mol Genet. 1998]
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Compound heterozygosity for a disease-causing G1489E [correction of G1489D] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos syndrome: an explanation of intrafamilial variability?

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