Identification of a mutation in the Indian Hedgehog (IHH) gene causing brachydactyly type A1 and evidence for a third locus.

Brachydactyly (BD) is a term used to describe inherited anomalies of the hands generally characterised by shortened phalanges or metacarpals. Initially, the brachydactylies were grouped into five different classes (A-E), with three subtypes of A. Later work revised and extended the classification of BD. 3 In type A, shortening is primarily confined to the middle phalanges. Subtype A1 (BDA1, OMIM 112500) is distinguished by hypoplastic middle phalanges (especially the 2nd and 5th digits), with either distal or terminal symphalangism depending on the severity. In addition, shortening of the proximal phalanges of the thumb, the metacarpals, metatarsals, or the big toe are also observed in these patients. Short stature is often associated with BDA1 patients. Despite being the first syndrome described with Mendelian autosomal dominant inheritance in 1903,, the genetic aetiology of BDA was not reported until 2001. Suspecting that cell proliferation or differentiation factors could be the culprit causing BDA1, our group screened markers near several candidate genes in two families diagnosed with BDA1. No linkage was observed. We also chose to look for mutations of the PAX3 genes in these families by direct sequencing of all the exons, but no significant mutation was identified (unpublished data). In 2000, a locus for BDA1 was mapped to 2q35-q36 in two unrelated Chinese families. Refined mapping and mutation screening of candidate genes in the region by the same group identified missense mutations in the Indian Hedgehog gene (IHH) of the affected subjects in three unrelated families. The missense mutations, located at the amino terminus of the IHH protein, are conserved among the Hedgehog family proteins. Local and long range cell proliferation signalling functions were suggested to reside within the amino-terminus domain. Interestingly, ROR2 and CDMP1 have been identified to cause brachydactyly types B and C, respectively. 9 The genes are important in chondrocyte proliferation and differentiation and joint morphogenesis.