A common haplotype at the 5′ end of the RET proto-oncogene, overrepresented in Hirschsprung patients, is associated with reduced gene expression

Paola Griseri, Tiziana Bachetti, Francesca Puppo, Francesca Lantieri, Roberto Ravazzolo, Marcella Devoto, Isabella Ceccherini

Research output: Contribution to journalArticle

Abstract

Hirschsprung disease (HSCR) is a complex genetic defect of intestinal innervation mainly ascribed to loss of function mutations of the RET gene. Although RETcoding mutations account for only 15% of HSCR sporadic cases, several linkage and association studies still indicate RET as a major HSCR gene, suggesting the existence of noncoding RET variants or common polymorphisms which can act in HSCR pathogenesis. We previously described a predisposing RET haplotype (A-C-A) composed of alleles at three SNPs (-1 bp and -5 bp from the RET transcription start site, NT_033985.6:g.975824G > A and NT_033985.6:g.975820C > A, respectively, and silent polymorphism c.135G > A), which was present in 62% of chromosomes from HSCR patients but only in 22% of control chromosomes. Here we address the question of how this 5′ ACA haplotype may functionally act as a predisposing factor in HSCR pathogenesis by performing functional analysis of the same three SNPs. We demonstrate that neither the two promoter variants nor the exon 2 SNP interfere with reporter gene transcription or RET mRNA splicing, respectively. However, real-time RT-PCR, performed in RNA obtained from lymphoblasts of selected individuals, has shown that homozygosity for the whole ACA haplotype is associated with reduced RET gene expression. We propose that a yet unidentified variant in linkage disequilibrium with the ACA haplotype, rather than the single characterizing SNPs, acts as a HSCR susceptibility allele by affecting the normal amount of RET receptor on the cell surface.

Original languageEnglish
Pages (from-to)189-195
Number of pages7
JournalHuman Mutation
Volume25
Issue number2
DOIs
Publication statusPublished - 2005

Keywords

  • Expression
  • Haplotypes
  • HSCR
  • Promoter
  • RET
  • SNP

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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