Single nucleotide polymorphic alleles in the 5' region of the RET proto-oncogene define a risk haplotype in Hirschsprung's disease

Sancandi, Monica; Griseri, Paola; Pesce, Bárbara; Patrone, Giovanna; Puppo, Francesca; Lerone, Margherita; Martucciello, G.; Romeo, Giovanni; Ravazzolo, Roberto; Devoto, Marcella; Ceccherini, Isabella

doi:10.1136/jmg.40.9.714

Cited by 49 publications

(53 citation statements)

References 23 publications

(28 reference statements)

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“…The same diseaseassociated haplotype was observed in the 5 0 region of the RET locus in 56-62% individuals of European descent (including Americans) [48][49][50][51][52][53][54][55]. The same haplotype was also present in Asians, although at a much higher frequency (85%) [52,54].…”

Section: Hirschsprung Diseasementioning

confidence: 52%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target. IntroductionThe human gene RET is localized on chromosome 10 (10q11.2) and contains 21 exons [1]; alternative splicing generates three isoforms, which contain 51 (RET51), 43 (RET43) and 9 (RET9) amino acids in the carboxyl (C)-terminal tail [2]. RET51 and RET9 are the most prevalent and best-characterized isoforms in vivo; RET43 has not yet been characterized. The RET51 isoform shows the highest transforming and kinase activity in vitro [3], and several observations suggest that these isoforms have different tissue-specific effects during embryogenesis [4]. Monoisoformic RET9 mice are viable and normal, whereas the monoisoformic RET51 mice (which lack RET9) have kidney hypoplasia and lack enteric ganglia from the colon [4].RET (Figure 1) is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs): namely GDNF, Neurturin, Persephin and Artemin [5]. To stimulate RET, these GFLs first need to form a complex with their glycosylphosphatidylinositol (GPI)-anchored co-receptor, a member of the GDNF receptor-a family (GFRa1-GFRa4), after which the GFL-GFRa complex activates RET [6,7]. The GFRs differ in their specificity for GFLs (Figure 1).

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Section: Hirschsprung Diseasementioning

confidence: 52%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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“…Six successive SNPs, namely: rs741763, SNP-5, SNP-1, rs2435362, rs2565206 and rs1800858 (Tables 1 and 2), were found to be strongly associated with HSCR in our population with the highest frequency increase of 23.1% among controls to 67.1% among patients. Associated alleles at marker loci genotyped also in other studies 24,35,36 were found to be the same (SNP-5, allele A; SNP-1, allele C; rs2565206, allele T; rs1800858, allele A). All of the alleles of genotyped markers also showed a significant transmission distortion (Table 3).…”

Section: Discussionmentioning

confidence: 85%

“…These markers included two SNPs located in the promoter region of the gene (SNP-5; G4A, 202 bp upstream of the start codon, and SNP-1; C4A, 198 upstream of the start codon), 24 and SNP rs741763; G4C located 4 kb upstream of the RET gene transcription start site. Two SNPs were located in intron 1 (IVS þ 6000A4C/rs2435362 and IVS1 -126G4T/rs2565206 (http://www.ncbi.nlm.nih.gov/SNP/) and the following SNPs were from exon 2 (c135G4A/A45A, rs1800858), 25 exon 7 (c1296G4A/rs1800860), 25 exon 14 (c2508C4T/ S836S, rs1800862) 25 and intron 19 (IVS19 þ 47C4T).…”

Section: Genotypingmentioning

confidence: 99%

Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

et al. 2004

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Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5 0 region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR420). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.

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“…Reports from different geographic regions showed that some synonymous polymorphisms on RET had different allele distribution between HSCR cases and controls (Borrego et al 2000;Sancandi et al 2003;Garcia-Barcelo et al 2003;Wu et al 2005). Those studies also successfully identified a representative genotype or haplotype in their HSCR patients, and association between some SNPs and the severity of the disease.…”

Section: Discussionmentioning

confidence: 87%

“…Most candidate genes belong to two major signaling pathways which have essential roles in migration and maturation of an enteric neuroblast, RET transmembrane receptor system (RET, GDNF), and endothelin receptor system (EDNRB, ET-3). Not concentrating solely on missense mutations, recent studies have also explored a potential association between allelotypes of synonymous polymorphisms within RET and the occurrence of the disease (Borrego et al 1999(Borrego et al , 2000Sancandi et al 2003;GarciaBarcelo et al 2003;Wu et al 2005). Apart from these two pathways, heterozygous mutations of SOX-10, a member of Sry type HMG family of transcription factors, have been detected in patients with syndromic HSCR (Pingault et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

et al. 2006

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Mutation and polymorphism data for Hirschsprung disease (HSCR) varies among ethnic groups. Single nucleotide polymorphisms (SNP) of RET protooncogene (RET) were recently shown to be associated with the disease, and with disease severity, in different populations. In this study, comprehensive analysis of RET, GDNF, EDNRB, ET-3, and SOX-10 genes among sporadic HSCR in Thailand was conducted by standard PCR-SSCP, RFLP, and sequencing methods. Of 41 patients, 30 cases had rectosigmoid disease (RSD) and 11 cases were assigned to the long-segment disease (LSD) group. Four missense mutations of RET, S100M, R231H, T278N, and G533S, were identified in three patients. One novel missense mutation, V111Q, was detected in EDNRB. For ET-3, two novel missense mutations, D166E and C173R, occurred concomitantly in a patient. The incidence of missense mutation was significantly higher in our female HSCR patient than in the male counterpart. Statistical analysis of the SNPs revealed a significant difference between allele distribution of RET L769L in patients in the LSD and RSD groups. The predominant genotype construct of RET A45A/L769L in our HSCR was GG/GG, which is obviously different from results from all previous studies. The GG/GG genotype construct was associated with RSD and with males. The study also detected a variant allele of RET S836S which has never been reported in Asian cohorts.

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Single nucleotide polymorphic alleles in the 5' region of the RET proto-oncogene define a risk haplotype in Hirschsprung's disease

Cited by 49 publications

References 23 publications

Current concepts in RET-related genetics, signaling and therapeutics

Current concepts in RET-related genetics, signaling and therapeutics

Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

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