Allele-Specific Expression at theRETLocus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease

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RETcommon variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well-known HSCR-associatedREThaplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level ofRETexpression when compared with the wild-type counterpart. As allele-specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whetherRETASE could contribute to the overall reduction ofRETmRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non-HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non-HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that theRETrisk haplotype is significantly more expressed in gut than in PBMCs (P= 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of totalRETexpression levels between gut samples with and without ASE, correlated reducedRETexpression with preferential transcription from theRETrisk haplotype. NonrandomRETASE occurs in ganglionic gut regardless of the disease status.RETASE should not be excluded as a disease mechanism acting during development.

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