Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects
- PMID: 12915476
- DOI: 10.1093/hmg/ddg233
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.
Similar articles
-
SALL1 mutations in Townes-Brocks syndrome and related disorders.Hum Mutat. 2000 Dec;16(6):460-6. doi: 10.1002/1098-1004(200012)16:6<460::AID-HUMU2>3.0.CO;2-4. Hum Mutat. 2000. PMID: 11102974 Review.
-
SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes.Hum Mutat. 2008 Sep;29(9):1133-40. doi: 10.1002/humu.20759. Hum Mutat. 2008. PMID: 18470945
-
Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome.Hum Mutat. 2006 Feb;27(2):211-2. doi: 10.1002/humu.9396. Hum Mutat. 2006. PMID: 16429401
-
SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype.Hum Mutat. 2005 Sep;26(3):282. doi: 10.1002/humu.9362. Hum Mutat. 2005. PMID: 16088922
-
Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature.J Pediatr Surg. 2008 Feb;43(2):391-3. doi: 10.1016/j.jpedsurg.2007.09.079. J Pediatr Surg. 2008. PMID: 18280297 Review.
Cited by
-
Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.Development. 2009 Feb;136(4):585-94. doi: 10.1242/dev.027748. Development. 2009. PMID: 19168674 Free PMC article.
-
Phenotypic and genotypic aspects of Townes-Brock syndrome: case report of patient in southern Brazil with a new SALL1 hotspot region nonsense mutation.BMC Med Genet. 2017 Nov 6;18(1):125. doi: 10.1186/s12881-017-0483-7. BMC Med Genet. 2017. PMID: 29110636 Free PMC article.
-
Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.J Pediatr. 2013 Mar;162(3):612-7. doi: 10.1016/j.jpeds.2012.08.042. Epub 2012 Oct 12. J Pediatr. 2013. PMID: 23069192 Free PMC article.
-
Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome.Genes (Basel). 2023 Jan 19;14(2):258. doi: 10.3390/genes14020258. Genes (Basel). 2023. PMID: 36833185 Free PMC article. Review.
-
Loss of the Sall3 gene leads to palate deficiency, abnormalities in cranial nerves, and perinatal lethality.Mol Cell Biol. 2004 Aug;24(16):7102-12. doi: 10.1128/MCB.24.16.7102-7112.2004. Mol Cell Biol. 2004. PMID: 15282310 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases