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Allele‐Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for H irschsprung Disease
Author(s) -
Matera Ivana,
Musso Marco,
Griseri Paola,
Rusmini Marta,
Di Duca Marco,
So Manting,
Mavilio Domenico,
Miao Xiaoping,
Tam Paul HK,
Ravazzolo Roberto,
Ceccherini Isabella,
GarciaBarcelo Merce
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22302
Subject(s) - biology , allele , haplotype , hirschsprung's disease , genetics , locus (genetics) , disease , enteric nervous system , phenotype , peripheral blood mononuclear cell , immunology , gene , medicine , endocrinology , in vitro
RET common variants are associated with H irschsprung disease ( HSCR ; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well‐known HSCR ‐associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild‐type counterpart. As allele‐specific expression ( ASE ) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET m RNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non‐ HSCR individuals) and peripheral blood mononuclear cells ( PBMC s; 16 HSCR and 14 non‐ HSCR individuals). Analysis of the data generated by SN a P shot and P yrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMC s ( P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE , correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development.