Expression of a truncated Sall1 transcriptional repressor is responsible for Townes–Brocks syndrome birth defects
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...
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Published in | Human molecular genetics Vol. 12; no. 17; pp. 2221 - 2227 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Oxford University Press
01.09.2003
Oxford Publishing Limited (England) |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ark:/67375/HXZ-8KJKV4VV-Q istex:FAA33CC7EB98BF49364D2B6FF8A35943EFD2DC5E local:ddg233 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0964-6906 1460-2083 1460-2083 |
DOI: | 10.1093/hmg/ddg233 |