Present address: Centro della Microcitemia e delle Anemia Congenite-Ematologia, Ospedale Galliera, Genova, Italy.
Allele-Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease
Article first published online: 15 MAR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 5, pages 754–762, May 2013
How to Cite
Matera, I., Musso, M., Griseri, P., Rusmini, M., Di Duca, M., So, M.-t., Mavilio, D., Miao, X., Tam, P. H., Ravazzolo, R., Ceccherini, I. and Garcia-Barcelo, M. (2013), Allele-Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease. Hum. Mutat., 34: 754–762. doi: 10.1002/humu.22302
Additional Supporting Information may be found in the online version of this article.
Communicated by Stylianos Antonarakis
Contract grant sponsors: Istituto Superiore di Sanità; Italian Ministry of Health (Bando Giovani Ricercatori GR-2008–1135082); Hong Kong Research Grants Council HKU (778610M); The University of Hong Kong Seed Funding Programme (200611159028); The University of Hong Kong Genomics Strategic Research Theme.
- Issue published online: 11 APR 2013
- Article first published online: 15 MAR 2013
- Accepted manuscript online: 25 FEB 2013 10:37AM EST
- Manuscript Accepted: 6 FEB 2013
- Manuscript Received: 29 OCT 2012
- Istituto Superiore di Sanità
- Italian Ministry of Health (Bando Giovani Ricercatori). Grant Number: GR-2008–1135082
- Hong Kong Research Grants Council HKU. Grant Number: 778610M
- The University of Hong Kong Seed Funding Programme. Grant Number: 200611159028
- The University of Hong Kong Genomics Strategic Research Theme
Vol. 34, Issue 7, 1047, Article first published online: 8 MAY 2013
- Hirschprung disease;
- regulatory polymorphisms;
- allele-specific expression
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.