SALL1 and the Townes-Brocks Syndrome
- DOI:
- 10.1093/med/9780199934522.003.0033
Townes–Brocks syndrome (TBS, MIM 107480) is a rare autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. TBS results 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. The protein is exclusively found in the nucleus and localizes to pericentromeric heterochromatin. SALL1 acts as a transcriptional repressor and contains two repression domains, but SALL1 orthologues can also activate expression of target genes. Nearly all known mutations within the SALL1 gene are located in exon 2. These are nonsense mutations (one of which causes TBS in nearly half of the sporadic cases), short insertions, duplications, and deletions as well as one large intra-exonic deletion. One mutation within intron 2 creates an aberrant splice site. All mutations lead to pre-terminal stop codons. The detection of whole gene deletions in TBS patients proved that SALL1 haploinsufficiency is clearly involved in the pathogenesis of TBS, which is contrary to the observations in Sall1 mouse mutants. The presumably more severe TBS phenotype associated with truncating SALL1 mutations, as compared to larger deletions, however, indicates an additional dominant-negative action of nonfunctional truncated SALL1 proteins.
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