title: 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 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.
authors: UOC Genetica Medica, Istituto Giannina Gaslini, Genova, Italy.
authors: Ivana
authors: I
authors: Matera
authors: Marco
authors: M
authors: Musso
authors: Paola
authors: P
authors: Griseri
authors: Marta
authors: M
authors: Rusmini
authors: Marco
authors: M
authors: Di Duca
authors: Man-Ting
authors: MT
authors: So
authors: Domenico
authors: D
authors: Mavilio
authors: Xiaoping
authors: X
authors: Miao
authors: Paul Hk
authors: PH
authors: Tam
authors: Roberto
authors: R
authors: Ravazzolo
authors: Isabella
authors: I
authors: Ceccherini
authors: Merce
authors: M
authors: Garcia-Barcelo
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D017615:Enteric Nervous System / Q000378:metabolism*; D005724:Ganglia / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human