Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.

Abstract

Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1/Lmbr1 gene, which resides approximately 1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human.

• Authors: Laura A Lettice, Taizo Horikoshi, Simon J H Heaney, Marijke J van Baren, Herma C van der Linde, Guido J Breedveld, Marijke Joosse, Nurten Akarsu, Ben A Oostra, Naoto Endo, Minoru Shibata, Mikio Suzuki, Eiichi Takahashi, Toshikatsu Shinka, Yutaka Nakahori, Dai Ayusawa, Kazuhiko Nakabayashi, Stephen W Scherer, Peter Heutink, Robert E Hill, Sumihare Noji
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 11 Pg. 7548-53 (May 28 2002) ISSN: 0027-8424 [Print] United States
• PMID: 12032320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hedgehog Proteins
• LMBR1 protein, human
• Lmbr1 protein, mouse
• Membrane Proteins
• SHH protein, human
• Trans-Activators

Topics

• Animals
• Cloning, Molecular
• Crosses, Genetic
• Hedgehog Proteins
• Heterozygote
• Humans
• In Situ Hybridization, Fluorescence
• Introns
• Membrane Proteins (genetics)
• Mice
• Mutation
• Phenotype
• Polydactyly (genetics)
• Recombination, Genetic
• Restriction Mapping
• Trans-Activators (genetics)
• Translocation, Genetic