A NEW SPONTANEOUS MOUSE MUTATION OF HOXD13 WITH A POLYALANINE EXPANSION AND PHENOTYPE SIMILAR TO HUMAN SYNPOLYDACTYLY

Human synpolydactyly (SPD) is an inherited congenital limb malformatio n caused by mutations in the HOXD13 gene. Heterozygotes are typically characterized by 3/4 finger and 4/5 toe syndactyly with associated dup licated digits; hands and feet of homozygotes are very small because o f a shortening of the phalanges, metacarpal and metatarsal bones. Here we describe the phenotype and molecular basis of a spontaneous mutati on of Hoxd13 in mice that provides a phenotypically and molecularly ac curate model for human SPD, The new mutation, named synpolydactyly hom olog (spdh), is a 21 bp in-frame duplication within a polyalanine-enco ding region at the 5'-end of the Hoxd13 coding sequence. The duplicati on expands the stretch of alanines from 15 to 22; the same type of exp ansion occurs in human SPD mutations, spdh/spdh homozygotes exhibit se vere malformations of all four feet, including polydactyly, syndactyly and brachydactylia, The phenotype of spdh is much more severe than th at exhibited by mice with a genetically engineered, presumably null, d isruption of Hoxd13 Thus spdh probably acts in a dominant-negative man ner and will be valuable for examining interactions with other Hox gen es and their protein products during limb development. Homozygous mice of both sexes also lack preputial glands and males do not breed; ther efore, spdh/spdh mice may also be valuable in studies of reproductive physiology and behavior.