Journal Article

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

Susan McLeskey Kiefer, Kevin K. Ohlemiller, Jing Yang, Bradley W. McDill, Jürgen Kohlhase and Michael Rauchman

in Human Molecular Genetics

Volume 12, issue 17, pages 2221-2227
Published in print September 2003 | ISSN: 0964-6906
Published online September 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg233
Expression of a truncated Sall1 transcriptional repressor is responsible for Townes–Brocks syndrome birth defects

Show Summary Details

Preview

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-ΔZn2-10, 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-ΔZn2-10 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.

Journal Article.  4608 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.