Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.
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.
Lettice
Laura A
LA
Medical Research Council Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
Horikoshi
Taizo
T
Heaney
Simon J H
SJ
van Baren
Marijke J
MJ
van der Linde
Herma C
HC
Breedveld
Guido J
GJ
Joosse
Marijke
M
Akarsu
Nurten
N
Oostra
Ben A
BA
Endo
Naoto
N
Shibata
Minoru
M
Suzuki
Mikio
M
Takahashi
Eiichi
E
Shinka
Toshikatsu
T
Nakahori
Yutaka
Y
Ayusawa
Dai
D
Nakabayashi
Kazuhiko
K
Scherer
Stephen W
SW
Heutink
Peter
P
Hill
Robert E
RE
Noji
Sumihare
S
D000818:Animals; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D053823:Hedgehog Proteins; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics*; D011995:Recombination, Genetic; D015183:Restriction Mapping; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic
D053823:Hedgehog Proteins; C485955:LMBR1 protein, human; C417920:Lmbr1 protein, mouse; D008565:Membrane Proteins; C509239:SHH protein, human; D015534:Trans-Activators