CHARACTERIZATION OF THE SPLIT HAND SPLIT FOOT MALFORMATION LOCUS SHFM1 AT 7Q21.3-Q22.1 AND ANALYSIS OF A CANDIDATE GENE FOR ITS EXPRESSION DURING LIMB DEVELOPMENT

Split hand/split foot malformation (SHFM) is a heterogeneous limb deve lopmental disorder, characterized by missing digits and fusion of rema ining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosoma l rearrangements, Utilizing a YAC contig across this region, we have d efined a critical interval of 1.5 Mb by the analysis of six interstiti al deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval, To delineate the basic mol ecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Thr ee genes were identified, two genes of the Distal-less (dll) homeobox gene family, DLX5 and DLX6 and a navel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significan t similarity to any known proteins but 100% amino acid sequence identi ty with its murine homolog (Dss1), Using RNA in situ hybridization ana lysis, we detected a tissue-specific expression profile for Dss1 in li mb bud, craniofacial primordia and skin, A deficiency in expression of DSS1, DLX5 and/or DLX6 during development may explain the SHFM phenot ypes.