MUTATION OF THE SRY-RELATED SOX10 GENE IN DOMINANT MEGACOLON, A MOUSEMODEL FOR HUMAN HIRSCHSPRUNG DISEASE

The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable mo del for the study of human congenital megacolon (Hirschsprung disease) . Here we report that the defect in the Dom mouse is caused by mutatio n of the gene encoding the Sry-related transcription factor Sox10, Thi s assignment is based on (i) colocalization of the Sox10 gene with the Dom mutation on chromosome 15; (ii) altered Sox10 expression in the g ut and in neural crest derived structures of cranial ganglia of Dom mi ce; (iii) presence of a frameshift in the Sox10 coding region, and (iv ) functional inactivation of the resulting truncated protein, These re sults identify the transcriptional regulator Sox10 as an essential fac tor in mouse neural crest development and as a further candidate gene for human Hirschsprung disease, especially in cases where it is associ ated with features of Waardenburg syndrome.