Hirschsprung disease: from genes and cells to patient

Abstract

Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells along variable portions of the distal intestine. HSCR is a complex rare disease with significant clinical and genetic heterogeneity and gender bias. The complexity observed in HSCR can be understood in the light of the molecular and cellular events that take place during the development of the enteric nervous system. The success of the colonization of the gut by neural crest cells (NCCs) depends on the synchronization and balance of the signaling network implicated. DNA alterations in the genes codifying for the signaling molecules may represent a primary etiology for HSCR. Severe mutations in a major gene encoding a crucial molecule or accumulation of less severe mutations in several genes may account for the variable phenotypes of HSCR. Recently, through a genome-wide association study, we have not only identified new genes implicated in the disease, but also highlighted the importance of functional crosstalk between the main signaling pathways for enteric ganglion formation. As early stages of human gestation are virtually inaccessible for experimental research, making human induced pluriopotent stem cell (iPSC) cultures provides a unique model for studying human NC development and the associated diseases. To date, we have successfully established various iPSC lines from syndromic and non-syndromic HSCR patients, and our preliminary data demonstrated that these patient lines exhibit severe diffentiation defects which may lead to diseases. As these lines carry exactly the same genetic make-up as the patients, they will provide powerful tools to unravel the complexity and to identify the missing heritability of the disease. High-throughput technologies, such as exome or RNA sequencing, applied to the genome of patients or to individual cell types are providing major breakthrough in the molecular studies of the HSCR pathogenesis and importantly, also in novel therapeutic intervention.