Genetic dissection and functional studies in Hirschsprung disease

PhD ceremony: Ms. Y. Sribudiani, 14.30 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Genetic dissection and functional studies in Hirschsprung disease

Promotor(s): prof. R.M.W. Hofstra

Faculty: Medical Sciences

Hirschsprung disease (HSCR) is a congenital neurological condition of the colon. Patients with HSCR have severe and sometimes even life-threatening constipation. This is due to a lack of ganglia that regulate the normal peristaltic movement of the colon. HSCR is considered to be a genetic disorder and 12 genes have now been identified. However, mutations in these genes explain only some of the HSCR patients. The research in this thesis focused on a better understanding of the nervous system of the colon (the enteric nervous system or ENS) and on finding and characterizing mutations and genes that contribute to disease development. To gain a better insight into the normal development of the ENS, progenitor cells of the ENS from embryonic mouse guts were isolated. The expression profiles of the cells were analyzed and compared with the expression profile of the entire gut. This resulted in a list of genes that are essential for ENS development and are perfect candidate genes for HSCR. Genes in regions previously identified as containing an HSCR gene were also studied. This resulted in one new HSCR gene, which proved to be associated specifically in the Chinese patient population. Finally, the function of a previously identified common mutation that is present in ~70% of HSCR patients was characterized.