SOX10 is abnormally expressed in aganglionic bowel of Hirschsprung's disease infants

Background - The primary pathology of Hirschsprung's disease (HD) is a cong enital absence of ganglion cells in the caudal most gut. The spastic agangl ionic bowel is often innervated by a network of hypertrophied nerve fibres. Recently, mutations of SOX10 have been identified in patients with HD but only in those with Waardenburg-Shah syndrome. Aims - To understand the molecular basis for the pathogenesis of HD we inte nded to determine the specific cell lineages in the enteric nervous system which normally express SOX10 but are affected in disease conditions. Methods - We studied colon biopsies from 10 non-syndromic HD patients, aged three months to four years, and 10 age matched patients without HD as norm al controls. The absence of mutation in the SOX10 gene of HD patients was c onfirmed by DNA sequencing. Expression and cellular distribution of SOX10 i n bowel segments of normal and HD infants were examined by reverse transcri ption-polymerase chain reaction and in situ hybridisation. Results - We found that in normal infants and normoganglionic bowel segment s of HD patients, SOX10 was expressed in both neurones and glia of the ente ric plexuses and in the nerves among the musculature in normal colon. In th e aganglionic bowel segments of patients, SOX10 expression was consistently lower and was found to be associated with the hypertrophic nerve trunks in the muscle and extrinsic nerves in the serosa. Conclusion - We conclude that SOX10 is normally required postnatally in the functional maintenance of the entire enteric nervous system, including neu rones and glia. In non-syndromic HD patients who do not have the SOX10 muta tion, the SOX10 gene expressed in the sacral region may be involved in the pathogenesis of the abnormal nerve trunks through interaction with other fa ctors.