SHOX mutations in dyschondrosteosis (Leri-Weill syndrome)

Dyschondrosteosis(1) (DCS) is an autosomal dominant(2) form of mesomelic dysplasia with deformity of the forearm (Madelung deformity; ref. 3). Based on the observation of XY translocations (p22,q12; refs 4-6) in DCS patients, we tested the pseudoautosomal region in eight families with DCS and showed linkage of the DCS gene to a microsatellite DNA marker at the DXYS233 locus (Zmax=6.26 at theta=0). The short stature homeobox-containing gene(7,8) (SHOX), involved in idiopathic growth retardation and possibly Turner short stature, maps to this region and was therefore regarded as a strong candidate gene in DCS. Here, we report large-scale deletions tin seven families) and a nonsense mutation tin one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism(9) results from homozygous mutations at the DCS locus.