Human limb malformations; an approach to the molecular basis of development

Analysis of human inherited limb malformations and of mouse mutants copying individual human mutations team up to promote the understanding of vertebrate limb development as a model for molecular regulatory interactions in animals. The strength of the human genetic contribution lies in the increasingly complete information on the human genome, transcriptome and proteome, as well as in the wealth of individual mutations interfering with limb development available for study. Based on the strong fundament of the human genome project, mapping and identification of novel genes associated with limb defects extends considerably the range of candidates beyond the repertoire of developmental genes and pathways known from animals. Attempts to correlate genotype and phenotype uncover a very broad range of genetic heterogeneity, i.e. different genes underlying the same phenotype, or allelic heterogeneity between families, i.e. clinically distinct phenotypes associated with mutations affecting the same gene. Mechanisms other than simple Mendelian inheritance have to be taken into consideration. Phenotypic variability within families might be explained by different modifying genes or environmental influence, whereas asymmetry of limb defects within one patient may be caused by epigenetic factors, such as somatic mosaicism or X-inactivation, or by non-genetic factors. The intimate knowledge of the genes and events governing limb pattern formation in humans and animals will elucidate the regulatory interactions underlying normal and pathological development, homeostasis, and repair, and thus propose targets for preventive measures and novel approaches to therapeutic intervention in the new era of molecular medicine.