New insight into birth defect characterized by digit duplication and fusion

Birth defects characterized by malformation of the limbs are relatively common. New insight into one form of the birth defect synpolydactyly, where individuals have 1 or more digit (finger or toe) duplicated and 2 or more digits fused together, has now been provided by Stefan Mundlos and colleagues, at Universitätsmedizin Berlin, Germany, who studied a mouse model of the condition. One form of synpolydactyly is caused by mutations in the HOXD13 gene. To understand how these mutations cause disease the authors analyzed mice carrying one of these mutations, Spdh/Spdh mice. Surprisingly, the protein generated by the mutated gene was found to have lost a function of the normal Hoxd13 protein and to have gained a new function. Specifically, the mutant protein was unable to facilitate normal levels of production of the soluble factor RA, and intrauterine treatment with RA restored normal digit formation in Spdh/Spdh mice. As RA was shown to normally suppress the generation of cells that produce and maintain cartilage, the loss-of-function mutated Hoxd13 therefore indirectly promotes the formation of cartilage. Importantly, further analysis indicated the mutated protein also directly induced the generation of cells that produce and maintain cartilage, whereas normal Hoxd13 did not. Thus, mutated Hoxd13 causes syndpolydactyly by inducing the generation of cells that produce and maintain cartilage, both directly and indirectly.

Source: Journal of Clinical Investigation