SALL1 mutations in Townes-Brocks syndrome and related disorders

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Abstract
Townes-Brocks syndrome (TBS) is a rare autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator sal of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved C2H2 double zinc finger domains which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Nineteen out of 20 SALL1 mutations known to date are located in exon 2, 5' of the third double zinc finger encoding region. These are nonsense mutations, short insertions, and short deletions, as well as one gross intraexonic deletion. One mutation within intron 2 creates an aberrant splice site. Most mutations lead to preterminal stop codons and are thought to cause the phenotype via haploinsufficiency. However, one short deletion results in a phenotype different from TBS which might be due to a dominant negative effect of a truncated SALL1 protein.