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 LMBR1͞Lmbr1 gene, which resides Ϸ1 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. )] is one of the most frequently observed human congenital limb malformations. Sporadic cases of PPD have been described, but most show an autosomal-dominant mode of inheritance. The limb-specific phenotype varies markedly within families, ranging from a simple addition of a phalanx in triphalangeal thumb to whole digit duplications and tibial aplasia. Using several large families, a PPD locus was mapped to a 450-kb region on chromosome 7q36, and all families described so far are linked to this locus (1-5). Recent reports suggest that PPD constitutes one aspect of a complex disease locus. Acheiropodia (6), complex polysyndactyly (CPS) (7), and acropectoral syndrome (8) are all distinct, limb-specific disorders that map to this region, suggesting that elements essential for limb development are located in this locus. Sasquatch (Ssq) is a mouse mutation that arose through a transgenic insertion (9). The mutation is semidominant, resulting in supernumerary preaxial (anterior) digits on the hindfeet in the heterozygotes. In homozygotes both fore-and hindlimbs show additional preaxial digits, and in some cases the long bones are shortened such that the limbs appear twisted. The insertion site responsible for the Ssq phenotype is physically linked to within Ϸ1 Mb of Shh.Here, we show that Ssq maps to the region on mouse chromosome 5 that corresponds to the human PPD locus. We identify mutations in a PPD patient and in the Ssq mouse. The PPD patient carries a de novo chromosomal translocation. Isolation of the PPD translocation breakpoint and the Ssq transgene insertion site revealed a similar location for these genetic disruptions within the Lmbr1 gene. We provide genetic analysis that shows that the Ssq mutation is not acting locally but in fact interrupts a long-range cis-acting regulator. This regulator operates on Shh residing 1.8 cM away, corresponding to a physical distance of Ϸ1 Mb. Consequently, disruption of Shh regulation is most likely the basis for PPD in humans. Materials and MethodsPatient Material. The translocation patient was clinically examined, and a member of her family was interviewed for family history at the Niigata University Hospital. All studies were approved by the local ethics committee. A member of the family gave written informed consent on behalf of the patient. The PPD families used in this study are...

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