The molecular basis of hypodactyly (Hd): a deletion in Hoxa13 leads to arrest of digital arch formation

Abstract

Hypodactyly (Hd) is a semidominant mutation in mice that maps in a genetic interval overlapping the Hoxa cluster. The profound deficiency of digital arch structures in Hd/Hd mice is consistent with a defect in a gene activated late in limb morphogenesis. We have determined the structure of the Hoxa13 gene and describe a 50-base pair deletion in the first exon of the Hd allele that probably arose from unequal recombination or misalignment between triplet repeats. It is predicted that no Hoxa13 protein is made from Hd mRNA. The hypodactyly limb phenotype is similar to that of Hoxd13-deficient mice in sharing defects along multiple axes and alterations in cartilage maturation; however, the overall effects on digital arch formation are more severe in Hd/Hd mice. Our results confirm the critical role of AbdB-like Hox genes in the development of the autopod, and add to the spectrum of mutations involving triplet repeats.