MUTATIONS IN THE SALL1 PUTATIVE TRANSCRIPTION FACTOR GENE CAUSE TOWNES-BROCKS-SYNDROME

Townes-Brocks syndrome (TBS, OMIM #107480) is a rare autosomal-dominan t malformation syndrome with a combination of anal, renal, limb and ea r anomalies(1), Cytogenetic findings(2) suggested that the gene mutate d in TBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spalt (sal), is located(3). SAL is a deve lopmental regulator in Drosophila melanogaster(4-8) and is conserved t hroughout evolution(3,9-11). No phenotype has yet been attributed to m utations in vertebrate sal-like genes. The expression patterns of sal- like genes in mouse(9), Xenopus(10) and the fish Medaka(11), and the f inding that Medaka sal is regulated by Sonic hedgehog (Shh; ref. 11), prompted us to examine SALL1 as a TBS candidate gene. Here we demonstr ate that SALL1 mutations cause TBS in a family with vertical transmiss ion of TBS12 and in an unrelated family with a sporadic case of TBS. B oth mutations are predicted to result in a prematurely terminated SALL 1 protein lacking all putative DNA binding domains. TBS therefore repr esents another human developmental disorder caused by mutations in a p utative C2H2 zinc-finger transcription factor.