Split-hand/split-foot malformation (SHFM) is a human disorder that is characterized by missing digits and deep median clefts in the hands and/or feet. There are currently three loci linked to this disorder on chromosomes 7q21, 10q25 and Xq26, but mutations in causative genes have not yet been identified.The 10q25 locus (SHFM3) had previously been restricted to a ∼10 cM region through genetic mapping in several large families with the disease. Although a number of genes were mapped inside this interval, none had been implicated in the pathogenesis of SHFM. A recent paper by Ianakiev et al.1xA novel human gene encoding an F-box/WD40 containing protein maps in the SHFM3 critical region on 10q24. Ianakiev, P. et al. Biochem. Biophys. Res. Commun. 1999; 261: 64–70Crossref | PubMed | Scopus (23)See all References1 identified yet another gene mapping to this critical region, which coded for a protein containing both an F box and a WD40 domain. Although this gene was still only a candidate for involvement in SHFM, the authors might have had some inside information as they named it Dactylin, after a spontaneous mouse mutant called dactylaplasia (Dac), which exhibits the SHFM phenotype. Shortly after this publication, the mouse Dactylin gene was cloned by Sidow et al.2xA novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant. Sidow, A. et al. Nat. Genet. 1999; 23: 104–107Crossref | PubMed | Scopus (76)See all References2 from the syntenic region of mouse chromosome 19, and shown to be disrupted in the Dac mutant.The identification of Dactylin as the dactylaplasia (and therefore the SHFM3) gene might seem like the simple solution to the puzzle. In some respects it is, but it also poses more questions than it answers. F-box proteins are involved in the protein ubiquitination and degradation pathway but, although Dactylin contains motifs of known function, the overall role of the protein in limb development remains a mystery. The Dac mutation also appears to produce a gain-of-function allele, not a null as might be predicted, because a mutant with a deletion of the entire Dactylin gene did not show a limb phenotype. It will be interesting to see whether this is mirrored in the human SHFM condition.The Dac phenotype can also be dominantly suppressed by an as yet unidentified modifier gene on mouse chromosome 13 (Mdac). From this we can assume that Mdac lies downstream of Dac in the biochemical pathway that leads to correct development of the limb. There is considerable variability in the severity of malformation in SHFM in conjunction with reduced penetrance – could this be owing to the influence of the human homologue of Mdac?The Dac gene might only be the first piece of the puzzle, but it advances our understanding of how and why limb development is so perturbed in these disorders, and it shows that mutant mice can be faithful models of human genetic disease.