SALL1 and the Townes–Brocks Syndrome
Authors: Kohlhase JÜRgen 
Published: November 2023

Abstract
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 7nger protein thought to act as a transcription factor. It contains four highly conserved C2H2 double zinc 7nger 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. 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. It is found that 57 out of 58 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 gross intraexonic deletion. One mutation within intron 2 creates an aberrant splice site. All mutations lead to preterminal stop codons. The detection of whole gene deletions in TBS patients proved that SALL1 haploinsuf7ciency 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.
SALL1 is the only gene currently known to be mutated in patients with TBS, and mutations of SALL1 have been found in 64.3%–83.3% of patients with “classical” TBS (Kohlhase et al., 1999c; Marlin et al., 1999). SALL1 is one out of the 7ve [four functional (SALL1-4) and one pseudogene (SALL1P)] human genes related to spalt (sal) of D. melanogaster (Kohlhase et al., 1996; Kohlhase et al., 1999a; Kohlhase et al., 1999b; Deloukas et al., 2001; Al-Baradie et al., 2002; Kohlhase et al., 2002). The 7rst indication that sal or sal-like genes are targets of hedgehog signaling came from the observation that in the Drosophila wing sal is activated in response to hedgehog signaling mediated by the TGF-β-like protein DPP (de Celis et al., 1996; Lecuit et al., 1996; Nellen et al., 1996; Sturtevant et al., 1997). Köster et al. showed that Medaka sal [homologous to SALL3 (Sweetman and Münsterberg, 2006)] expression is con7ned to hedgehog signaling centers. Furthermore, sal expression domains adjacent to shh (sonic hedgehog) expression domains are expanded by ectopic SHH, whereas suppression of shh expression by overexpression of protein kinase A results in suppression of sal expression (Köster et al., 1997). For csal1, the chick orthologue of SALL1, it has been demonstrated that expression in the limb is activated by ectopic SHH. However, this activation requires signals from the apical ectodermal ridge and involves FGF4/8 as well as Wnt3a and Wnt7a (Farrell and Munsterberg, 2000), showing that csal1 expression is under control of at least three different pathways. In zebra7sh, the SALL1 homologue sall1a is regulated by tbx5 and required for fgf10 and fgfr2 expression in the posterior pectoral 7n bud (Harvey and Logan, 2006). In the mouse, Sall1 was found to enhance the canonical Wnt signaling pathway by localizing to pericentromeric heterochromatin (Sato et al., 2004).