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.
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The molecular explanation underlying phenotypic evidence in animal models and phenotype-genotype correlations in TBS patients remained unclear to date.
“However to date, the molecular explanation underlying phenotypic evidence in animal models 25,29 and phenotypegenotype correlations in TBS patients 47,60,32 remained unclear.”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [29]
Cites
Al-Baradie, R., Yamada, K., St. Hilaire, C., Chan, W.-M., Andrews, C., McIntosh, N., Nakano, M., Martonyi, E. J., Raymond, W. R., Okumura, S., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/343821 · Cited by 314 · see citing works
Hereditary syndrome of imperforate anus with hand, foot, and ear anomalies
Townes, P. L., & Brocks, E. R. (1972) · The Journal of Pediatrics · doi:10.1016/s0022-3476(72)80302-0 · Cited by 174 · cited 1× · see citing works
“These abnormalities of the carpal bones are identical to those described in the original patient reports by Townes and Brocks ( 13 ).”
ResultMolecular Analysis of SALL1 Mutations in Townes-Brocks Syndrome
Kohlhase, J., Taschner, P. E. M., Burfeind, P., Pasche, B., Newman, B., Blanck, C., Breuning, M. H., ten Kate, L. P., Maaswinkel-Mooy, P., Mitulla, B., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302238 · Cited by 152 · cited 11× · see citing works
“SALL1 mutations have been reported to have kidney defects, most commonly renal hypoplasia with or without cysts ( 9 ).”
BackgroundInfluentialSelf-citationMurine Sall1 represses transcription by recruiting a histone deacetylase complex
Kiefer, S. M., McDill, B. W., Yang, J., & Rauchman, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200052200 · Cited by 79 · cited 11× · see citing works
“In support of this idea, mutations that cause TBS could result in production of a truncated protein encoding the N-terminus of SALL1, the region that we have shown mediates transcriptional repression ( 1 ).”
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Warren, M., Wang, W., Spiden, S., Chen‐Murchie, D., Tannahill, D., Steel, K. P., & Bradley, A. (2007) · genesis · doi:10.1002/dvg.20264 · Cited by 69 · see citing works
SALL4 controls cell fate in response to DNA base composition
Pantier, R., Chhatbar, K., Quante, T., Skourti-Stathaki, K., Cholewa-Waclaw, J., Alston, G., Alexander-Howden, B., Lee, H. Y., Cook, A. G., Spruijt, C. G., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.11.046 · Cited by 45 · see citing works
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Transcription factors that define the epigenome structures and transcriptomes in microglia
Saeki, K., & Ozato, K. (2025) · Experimental Hematology · doi:10.1016/j.exphem.2025.104814 · Cited by 11 · see citing works
Innoceta, A. M., Olivucci, G., Parmeggiani, G., Scarano, E., Pragliola, A., & Graziano, C. (2023) · Genes · doi:10.3390/genes14020258 · Cited by 7 · see citing works
“Although more mutations should be functionally characterized in order to confirm these findings, a growing degree of severity can be hypothesized such as: (1) the complete absence of SALL1 is likely to be embryonic lethal, (2) a small amount of SALL1 function (with the homozygous p.R1054* mutation being the only examp…”
BackgroundInfluentialTownes-Brocks syndrome with craniosynostosis in two siblings
Lugli, L., Rossi, C., Ceccarelli, P. L., Calabrese, O., Bedetti, L., Miselli, F., Bianchini, M. A., Iughetti, L., & Berardi, A. (2022) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2022.104642 · Cited by 5 · see citing works
Tetramerisation governs SALL transcription factor function in development and disease
Giuliani, S., Chhatbar, K., Wear, M., Guy, J., Mathieson, T., Burdett, H., George, L., Alston, G., Spanos, C., McHugh, T., et al. (2025) · bioRxiv · doi:10.1101/2025.10.27.684836
- Authors
- Kiefer, S. M.
- Affiliations
- St. Louis VA Medical Center (US)
- Corresponding author
- Kiefer, S. M.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-07-08
- Volume
- 12
- Issue
- 17
- Pages
- 2221-2227
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2096532391
- Cited by
- 124
- References
- 4
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 3 · 2013: 3 · 2012: 5
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07126, T32DK007126)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Townes-Brocks syndrome, SALL1, transcriptional repressor, dominant negative mutation, gain-of-function mutations, haploinsufficiency, sensorineural hearing loss, renal agenesis, exencephaly, limb malformations, mouse model
- MeSH terms
- Congenital Abnormalities, Abnormalities, Multiple, Animals, Anal Canal, Bone and Bones, Carrier Proteins, Chlorocebus aethiops, DNA-Binding Proteins, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Heterozygote, Histone Deacetylases, Homozygote, Kidney, Luciferases, Nerve Tissue Proteins, Plasmids, Transcription Factors, Limb Deformities, Congenital, Mice, Knockout, Gene Expression Regulation, Developmental, COS Cells, Mice
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