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

ABSTRACT RET common variants are associated with Hirschsprung 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 haploty...

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Bibliographic Details
Published in:Human mutation 2013-05, Vol.34 (5), p.754-762
Main Authors: Matera, Ivana, Musso, Marco, Griseri, Paola, Rusmini, Marta, Di Duca, Marco, So, Man-ting, Mavilio, Domenico, Miao, Xiaoping, Tam, Paul HK, Ravazzolo, Roberto, Ceccherini, Isabella, Garcia-Barcelo, Merce
Format: Article
Language:English
Subjects:
allele-specific expression
Alleles
Cell Line, Tumor
Enteric Nervous System - metabolism
Ganglia - metabolism
Genetic Predisposition to Disease
Haplotypes
Hirschprung disease
Hirschsprung Disease - genetics
Humans
Monocytes - metabolism
Proto-Oncogene Proteins c-ret - blood
Proto-Oncogene Proteins c-ret - genetics
Proto-Oncogene Proteins c-ret - metabolism
Real-Time Polymerase Chain Reaction
regulatory polymorphisms
RET
RNA, Messenger - genetics
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Summary:ABSTRACT RET common variants are associated with Hirschsprung 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 mRNA 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 the RET risk 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 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. We studied a well‐known HSCR (Hirschsprung disease; colon aganglionosis)‐associated RET risk haplotype that correlates with reduced RET expression. We investigated whether RET allele‐specific expression (ASE) could contribute to the overall reduction of RET mRNA detected in carriers of the risk haplotype. Comparison of RET expression levels between human gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the risk haplotype. RET ASE occurred in ganglionic gut regardless of the disease status.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22302