Causative gene for human "lobster claw" syndrome identified

A new study using mouse “knockouts” shows that genes that control limb formation in insects have similar functions in mammals.

Split hand/foot malformation (SHFM) or ectrodactyly (the “lobster claw” anomaly), is a severe congenital malformation syndrome characterised by a profound median cleft of the hands and/or feet, typically associated with absence or fusion of the remaining fingers. This condition is quite frequent as about 6 cases of SHFM are observed for every 10,000 human births.

Several forms of SHFM are each associated with a different genetic mutation. One of the most frequent forms called Type I is associated with a specific region of human chromosome 7 that contains two homeobox genes, DLX5 and DLX6. These genes are similar to a gene in insects called distal-less that controls limb development. When this gene is defective in the fruit fly the distal part of the insect limb is missing. It was therefore assumed that DLX5 and DLX6 might have conserved this function through evolution and could have a role in vertebrate limb development. However, in spite of intensive searches for mutations of these genes in SHFM patients, no direct evidence was found to date on their involvement in mammalian limb development.

A research team led by Dr. Giovanni Levi from the Centre National de la Recherche Scientifique (CNRS) working in the Museum of Natural History in Paris and co-workers from the Italian Institute for Cancer Research (IST) supported by Telethon (Italy), has now generated knockout mice in which both the Dlx5 and Dlx6 genes have been inactivated through gene targeting and embryonic stem cells. These Dlx5/Dlx6 mutant mice have a limb defect that is very similar to that observed in SHFM1 patients. This finding, to be published in the June 2002 issue of genesis, is critical for an understanding of the molecular origin of the disease as it demonstrates that these are the genes responsible for the SFHM syndrome.

These studies should also warrant renewed efforts to find specific human mutations associated with DLX5 and DLX6 genes through genomic and mutational analyses. It is possible that knowledge of these genetic defects might permit early prenatal diagnosis of the disease. Furthermore, the availability of an animal model of the human disease will permit a molecular understanding of the etiology of SHFM1. Detailed studies of these mice will make it possible to understand how the genetic lesion is associated with a limb malformation in humans.

The data reported in Dr. Levi`s article show that in spite of the very different structure of insect and vertebrate limbs, the same genes control their development. This is further proof that the limb of a fly is homologous to a human limb.