MOLECULAR BASIS OF HEREDITARY DISEASES: THE CASE OF HIRSCHSPRUNG’S DISEASE

J. Amiel, R. Salomon, T. Attié, R. Touraine, J. Steffann, A. Pelet, C. Niboul-Fékété, M. Vekemans, A. Munnich, S. Lyonnet

Département de Génétique, Clinique Chirurgicale Infantile et INSERM U-393, Hopital Necker-Enfants Malades, Paris, France

Hirschsprung disease (HSCR) is a frequent malformation regarded as a model of multigenic neurocristopathy resulting from the absence of neural crest-derived enteric neurons. Hitherto, genetic mapping in human, and knock-out or positional cloning of mouse genes showed that 6 susceptibility genes contribute the HSCR phenotype, most of them being involved in either the RET receptor tyrosine-kinase or the endothelin signalling pathways. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. In addition, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate predisposing genes for HSCR.

Interestingly, several mutations were neither necessary nor sufficient for phenotypic expression, and multiple variants co-segregated in some HSCR families. We now report on a whole-genome screening in a large series of HSCR sib-pairs showing that at least 3 independent loci including the major locus RET may be required for clinical expression of HSCR. The genetic dissection of HSCR might help understanding the role of modifier and major genes compromising various steps of related developmental cascades. Thus, the dissection of the genetic aetiology of HSCR disease may also provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin.