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Human Molecular Genetics Advance Access originally published online on July 15, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 17 2221-2227
DOI: 10.1093/hmg/ddg233
© 2003 Oxford University Press

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

Susan McLeskey Kiefer1, Kevin K. Ohlemiller2, Jing Yang1, Bradley W. McDill1, Jürgen Kohlhase3 and Michael Rauchman1,*

1Renal Division, School of Medicine, Washington University, St Louis and 2Central Institute for the Deaf, St Louis, MO 63110, USA and 3Institut für Humangenetik der Universität Göttingen, Gosslerstrasse 12d, D-37073 Göttingen, Germany

Received May 19, 2003; Revised June 27, 2003; Accepted July 5, 2003

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-{Delta}Zn2-10, 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-{Delta}Zn2-10 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.

* To whom correspondence should be addressed at: Department of Medicine and Biochemistry and Molecular Biology, Saint Louis University and Veterans Affairs Medical Center, Renal Division 657/111B-JC, 915 N Grand Avenue, St Louis, MO 63106, USA. Tel: +1 3142896485; Email: rauchman{at}slu.edu


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