The SALL1 gene is part of a group of related genes that provide instructions for making proteins involved in the formation of tissues and organs before birth. These proteins are transcription factors, which means they attach (bind) to specific regions of DNA and help control the activity of particular genes.
The SALL1 protein helps turn off (repress) gene activity by interacting with other proteins that alter how tightly regions of DNA are packaged. This process, known as chromatin remodeling, is one way gene expression is regulated during development; typically, when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. By controlling gene activity, the SALL1 protein plays an important role in development of the hands (particularly the thumbs), ears, anus, kidneys, and other parts of the body before birth.
Health Conditions Related to Genetic Changes
At least 75 mutations in the SALL1 gene have been identified in people with Townes-Brocks syndrome, which is typically characterized by a malformation of the anal opening (imperforate anus), abnormally shaped ears, and hand malformations. It is uncertain how these mutations result in the specific features of the condition.
Most SALL1 gene mutations involved in this disorder lead to the production of an abnormally short version of the SALL1 protein that malfunctions within cells. The malfunctioning protein is thought to interfere with normal copies of the SALL1 protein, which are produced from the other copy of the SALL1 gene that does not have a mutation. This interference prevents the normal proteins from entering the nucleus to regulate gene activity. The malfunctioning protein may also interact with other proteins, disrupting their function. For example, some research indicates that the abnormally short SALL1 protein interferes with proteins that control the formation of cellular structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of cells and participate in signaling pathways that transmit information within and between cells. Cilia are important for the structure and function of many types of cells and the normal development of several tissues. Abnormalities in cilia can disrupt important chemical signaling pathways during development and may contribute to the features of Townes-Brocks syndrome.
Other, less-common SALL1 gene mutations prevent the gene from making protein; this reduces by half the amount of SALL1 protein produced in cells. Some studies suggest that mutations that reduce the amount of SALL1 protein are responsible for milder cases of Townes-Brocks syndrome, and mutations that result in an abnormally short, malfunctioning SALL1 protein underlie the more severe cases of the condition. However, other studies do not find the same correlation.
A shortage of functioning SALL1 protein, due to either type of mutation, likely impairs the regulation of genes that direct the development of many different organs and tissues before birth. Abnormal development before birth due to unusual gene activity leads to the varied birth defects associated with Townes-Brocks syndrome.More About This Health Condition
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Congenital anomalies of kidney and urinary tract
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Other Names for This Gene
- sal (Drosophila)-like 1
- sal-like 1
- sal-like 1 (Drosophila)
- Sal-like protein 1
- spalt-like transcription factor 1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Borozdin W, Steinmann K, Albrecht B, Bottani A, Devriendt K, Leipoldt M, Kohlhase J. 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. Citation on PubMed
- Botzenhart EM, Bartalini G, Blair E, Brady AF, Elmslie F, Chong KL, Christy K, Torres-Martinez W, Danesino C, Deardorff MA, Fryns JP, Marlin S, Garcia-Minaur S, Hellenbroich Y, Hay BN, Penttinen M, Shashi V, Terhal P, Van Maldergem L, Whiteford ML, Zackai E, Kohlhase J. Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. Hum Mutat. 2007 Feb;28(2):204-5. Citation on PubMed
- Botzenhart EM, Green A, Ilyina H, König R, Lowry RB, Lo IF, Shohat M, Burke L, McGaughran J, Chafai R, Pierquin G, Michaelis RC, Whiteford ML, Simola KO, Rösler B, Kohlhase J. SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype. Hum Mutat. 2005 Sep;26(3):282. Citation on PubMed
- Bozal-Basterra L, Martín-Ruíz I, Pirone L, Liang Y, Sigurðsson JO, Gonzalez-Santamarta M, Giordano I, Gabicagogeascoa E, de Luca A, Rodríguez JA, Wilkie AOM, Kohlhase J, Eastwood D, Yale C, Olsen JV, Rauchman M, Anderson KV, Sutherland JD, Barrio R. Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome. Am J Hum Genet. 2018 Feb 1;102(2):249-265. doi: 10.1016/j.ajhg.2017.12.017. Citation on PubMed or Free article on PubMed Central
- de Celis JF, Barrio R. Regulation and function of Spalt proteins during animal development. Int J Dev Biol. 2009;53(8-10):1385-98. doi: 10.1387/ijdb.072408jd. Review. Citation on PubMed
- Kiefer SM, Ohlemiller KK, Yang J, McDill BW, Kohlhase J, Rauchman M. Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects. Hum Mol Genet. 2003 Sep 1;12(17):2221-7. Epub 2003 Jul 15. Citation on PubMed
- Kohlhase J, Liebers M, Backe J, Baumann-Müller A, Bembea M, Destrée A, Gattas M, Grüssner S, Müller T, Mortier G, Skrypnyk C, Yano S, Wirbelauer J, Michaelis RC. High incidence of the R276X SALL1 mutation in sporadic but not familial Townes-Brocks syndrome and report of the first familial case. J Med Genet. 2003 Nov;40(11):e127. Erratum in: J Med Genet. 2004 Jan;41(1):74. Citation on PubMed or Free article on PubMed Central
- Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W. Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet. 1998 Jan;18(1):81-3. Citation on PubMed
- Kohlhase J. Townes-Brocks Syndrome. 2007 Jan 24 [updated 2016 Jan 14]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK1445/ Citation on PubMed
- Miller EM, Hopkin R, Bao L, Ware SM. Implications for genotype-phenotype predictions in Townes-Brocks syndrome: case report of a novel SALL1 deletion and review of the literature. Am J Med Genet A. 2012 Mar;158A(3):533-40. doi: 10.1002/ajmg.a.34426. Epub 2012 Feb 3. Review. Citation on PubMed
- Netzer C, Rieger L, Brero A, Zhang CD, Hinzke M, Kohlhase J, Bohlander SK. SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. Hum Mol Genet. 2001 Dec 15;10(26):3017-24. Citation on PubMed