A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice

Polydactyly is a common malformation of vertebrate limbs. In humans a major locus for nonsyndromic preaxial polydactyly (PPD) has been mapped previous ly to 7q36. The mouse Hemimelic extra-toes (Hx) mutation maps to a homologo us chromosome segment and has been proposed to affect a homologous gene. To understand the molecular changes underlying PPD, we used a positional clon ing approach to identify the gene or genes disrupted by the Hx mutation and a closely linked limb mutation, Hammertoe (Hm). High-resolution genetic ma pping identified a small candidate interval for the mouse mutations located 1.2 cM distal to the Shh locus. The nonrecombinant interval was completely cloned in bacterial artificial chromosomes and searched for genes using a combination of exon trapping, sample sequencing, and mapping of known genes . Two novel genes, Lmbr1 and Lmbr2, are entirely within the candidate inter val we defined genetically. The open reading frame of both genes is intact in mutant mice, but the expression of the Lmbr1 gene is dramatically altere d in developing limbs of Hx mutant mice, The correspondence between the spa tial and temporal changes in Lmbr1 expression and the embryonic onset of th e Hx mutant phenotype suggests that the mouse Hx mutation may be a regulato ry allele of Lmbr1. The human ortholog of Lmbr1 maps within the recently de scribed interval for human PPD, strengthening the possibility that both mou se and human limb abnormalities are due to defects in the same highly conse rved gene. (C) 2000 Academic Press.