A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Ehlers-Danlos syndrome (EDS) comprises diverse inherited connective tissue disorders.
• Mutations in type V collagen genes are implicated in common EDS forms (types I and II).

Purpose of the Study:

• To characterize a COL5A2 gene mutation in a family with Ehlers-Danlos syndrome type II.
• To investigate the functional consequences of this mutation on type V collagen synthesis.

Main Methods:

• Cultured dermal fibroblasts from an affected individual were analyzed.
• Haplotype analysis was performed to determine the disease locus.
• Direct sequencing of the COL5A2 cDNA open reading frame identified the mutation.

Main Results:

• Abnormal type V collagen synthesis was observed in fibroblasts from the affected subject.
• Haplotype analysis supported COL5A2 as the disease-associated gene.
• A single base mutation (G934R) was detected in the COL5A2 gene, substituting a glycine residue in the alpha2(V) collagen triple helical domain.
• This mutation was present in all three affected family members and absent in 50 normal chromosomes.

Conclusions:

• The identified G934R mutation in COL5A2 is causative for Ehlers-Danlos syndrome type II in this family.
• This dominant negative mutation disrupts alpha2(V) collagen structure and function, consistent with other inherited connective tissue disorders.