Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects

Abstract

Townes-Brocks syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.

Phenotypic variability in a family with Townes–Brocks syndrome

“…However, a mouse carrying a Sall1-null allele does not mimic the human TBS and a mouse carrying a Sall1 mutant allele that produces a truncated protein and presents clinical features of TBS. 10 Kiefer et al (2003) demonstrated that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. 10 Furniss et al (2007) reported a heterozygous 995delC mutation in exon 2 of SALL1 escaped nonsense-mediated decay and produced a truncated protein acting in a dominant-negative manner.…”

“…10 Kiefer et al (2003) demonstrated that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. 10 Furniss et al (2007) reported a heterozygous 995delC mutation in exon 2 of SALL1 escaped nonsense-mediated decay and produced a truncated protein acting in a dominant-negative manner. 11 Nonsense-mediated decay efficiency varies between individuals and is tissue specific, which may contribute to phenotypic variation in the patients carrying the same mutations.…”

Detection of heterozygousSALL1 deletions by quantitative real time PCR proves the contribution of aSALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome

“…Based on animal model data, SALL1 mutations causing Townes-Brocks syndrome were predicted to have dominant (-negative) effects (McLeskey Kiefer et al, 2003;Nishinakamura, 2003;Sweetman et al, 2003), and resulting truncated SALL1 proteins could interfere with other SALL proteins. Our results shown here prove that SALL1 is required for proper development of thumbs, ears, hearing (i. e. inner and/ or middle ear) and anus in humans, and (2) that SALL1 haploinsufficiency leads to TBS.…”

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

“…Vessel length was measured and vessel area was calculated as described. 9 Angiogenesis assay in embryoid bodies (EBs)…”

“…[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.…”