Study On Mapping And Mutation Of The Disease Gene Of Symphalangism

Symphalangism(SYM1) is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joints, fusion of carpal and tarsal bones, and in some cases of conductive deafness. We identified and characterized two five-generation Chinese families with SYM1. In two families, all patients showed the similar clinical features. The affected members have normal intelligence. Patients were unable to flex fingers at the proximal interphalangeal joint. Radiography showed bilateral proximal interphalangeal joint osseous fusion of fingers 2-4, distal interphalangeal joint fusion of the fifth digits, and sometimes the proximal interphalangeal joint osseous fusion of the fifth fingers. More than half of affected patients displayed flat feet. Foot radiography showed that the second and the third cuneiform bones were fused to the second and the third metatarsus bones; the second cuneiform bone was fused to the cuneiform bone respectively, and scaphoid was fused to talus. Audiology showed no hearing abnormality in the affected individuals of two families.The two families share some similarities with SYM1 families with mutations in the NOG gene. However, they show some unique features including the absence of cuboid bone, the lack of shortness of the first and the fifth metacarpal bones, and manifestation of flat feet. The two families share some similarities with IHH of brachydactyly type A, including interphalangeal shortness and fusion. So IHH gene and NOG gene is supported as the possible candidate disease gene. Peripheral blood samples from the two families members were obtained , and genomic DNA was isolated from the whole blood. IHH and NOG gene were selected as the candidate gene. Four polymorphic microsatellite markers of D20S2382, D20S126 and D17S1868, D17S787, flanking the two genes respectively, were selected for linkage analysis. The LOD score was calculated through Linkage Package 5.1 software. Result showed that the disease gene have no linkage with IHH and NOG gene. This result may be sured by haploid analysis.After excluding the possibility of the NOG and IHH gene as the disease gene in the two families, a genome-wide scan analysis was carried out with 382 polymorphic microsatellites markers on chromosomes 1-22. The maximal LOD score 4.32 were observed at microsatellite markers D20S106 of GDF5 gene. Mutation analysis revealed a novel E491K mutation in the GDF5 gene in both families. The mutation occurs at a highly conserved residue in the TGF-βdomain of GDF5 and represents the second GDF5 mutation for SYM1 to date. These results indicated that defects in GDF5 can cause SYM1 in the Chinese population.This research identifies the disease gene of SYM1 with GDF5 gene defects in the first time in the Chinese population, expands the spectrum of clinical phenotypes associated with mutant GDF5.