Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome

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Abstract
Townes-Brocks syndrome (IBS, OMIM #107480) is a rare autosomal-dominant malformation syndrome with a combination of anal, renal, limb and ear anomalies1. Cytogenetic findings2 suggested that the gene mutated in IBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spa/t (sal), is located3. SAL is a developmental regulator in Drosophila melanogasfer4–8 and is conserved throughout evolution3,9–11. No phenotype has yet been attributed to mutations in vertebrate saMike genes. The expression patterns of saMike genes in mouse9, Xenopi/s10 and the fish Medaka11, and the finding that Medaka sal is regulated by Sonic hedgehog (Shh; ref. 11), prompted us to examine SALL1 as a TBS candidate gene. Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS12 and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DMA binding domains. TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc–finger transcription factor.