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

Abstract

Townes-Brocks syndrome (TBS, OMIM #107480) is a rare autosomal-dominant malformation syndrome with a combination of anal, renal, limb and ear anomalies. Cytogenetic findings suggested that the gene mutated in TBS maps to chromosome 16q12.1, where SALL1 (previously known as HSAL1), a human homologue of spalt (sal), is located. SAL is a developmental regulator in Drosophila melanogaster and is conserved throughout evolution. No phenotype has yet been attributed to mutations in vertebrate sal-like genes. The expression patterns of sal-like genes in mouse, Xenopus and the fish Medaka, 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 TBS 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 DNA binding domains. TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc-finger transcription factor.

Transcriptional Activation of the SALL1 by the Human SIX1 Homeodomain during Kidney Development

“…Rapid Amplification of cDNA Ends-The 5Ј-end of the SALL1 cDNA was determined with the 5Ј-RACE 4 -PCR method. Human kidney Marathon-Ready cDNA (Clontech) was amplified with the PCR primer adaptor AP1 and the cDNA-specific primer R1 of SALL1 according to the manufacturer's instructions.…”

“…Kidney malformations occur in ϳ60% of Townes-Brocks syndrome patients, including unilateral or bilateral hypoplastic or dysplastic kidneys, renal agenesis, and multicystic kidneys. The human homologue of the Drosophila SAL gene, SALL1, maps to chromosome 16q12.1, and alterations of this locus were found in Townes-Brocks syndrome families (3,4). All mutations identified so far are found in the 5Ј-region of the triple zinc finger motif and result in premature termination of translation (5,6).…”

Zinc-finger transcriptional factor Sall1 induces angiogenesis by activation of the gene for VEGF-A

“…10 Although Sall1 modulates gene expression and regulates organogenesis, the role of Sall1 in vascular development is not clear. Nishinakamura et al 18 demonstrated that homozygous Sall1-deficient mice show severe renal dysplasia or complete renal agenesis; however, the mice exhibit normal vascular development.…”

“…[8][9][10] Recently, engineered zinc-finger transcription factors have been reported to promote therapeutic angiogenesis by induction of the VEGF-A gene. 11,12 Synthetic zinc-finger proteins activate expression of the VEGF-A gene at a level exceeding that induced by hypoxic stress.…”

Hedgehog signalling is required for cloacal development in the zebrafish embryo

“…The commonest and least severe defect is anal stenosis -the narrowing of the anal opening. More severe is the imperforate anus, which (Belloni et al, 2000, Hagan et al, 2000, Hall et al, 1980, Kohlhase et al, 1998, Martinez-Frias et al, 2001, Rittler et al, 1996, Ross et al, 1998. Animal models for various digestive system malformations have been developed to investigate their genetic and environmental basis.…”