Elsevier

Genomics

Volume 67, Issue 1, 1 July 2000, Pages 19-27
Genomics

Regular Article
A Novel Candidate Gene for Mouse and Human Preaxial Polydactyly with Altered Expression in Limbs of Hemimelic extra-toes Mutant Mice

https://doi.org/10.1006/geno.2000.6225Get rights and content

Abstract

Polydactyly is a common malformation of vertebrate limbs. In humans a major locus for nonsyndromic preaxial polydactyly (PPD) has been mapped previously to 7q36. The mouse Hemimelic extra-toes (Hx) mutation maps to a homologous chromosome segment and has been proposed to affect a homologous gene. To understand the molecular changes underlying PPD, we used a positional cloning approach to identify the gene or genes disrupted by the Hx mutation and a closely linked limb mutation, Hammertoe (Hm). High-resolution genetic mapping 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 interval we defined genetically. The open reading frame of both genes is intact in mutant mice, but the expression of the Lmbr1 gene is dramatically altered in developing limbs of Hx mutant mice. The correspondence between the spatial and temporal changes in Lmbr1 expression and the embryonic onset of the Hx mutant phenotype suggests that the mouse Hx mutation may be a regulatory allele of Lmbr1. The human ortholog of Lmbr1 maps within the recently described interval for human PPD, strengthening the possibility that both mouse and human limb abnormalities are due to defects in the same highly conserved gene.

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  • Cited by (0)

    Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF190656 and AF190666 (Lmbr1 sequences); AF190664 (Lmbr2); AQ939855–AQ939871 (exon-trapped sequences 1–17); AQ939858, AQ939862, and AQ939863 (D5Kng1); AZ048470 (D5Kng2); and AQ939860 (D5Kng3).

    1

    These authors contributed equally to this work.

    2

    Present address: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452.

    3

    To whom correspondence should be addressed. Telephone: (650) 725-5954. Fax: (650) 725-7739. E-mail: [email protected].

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