A Rare Haplotype of the RET Proto-Oncogene Is a Risk-Modifying Allele in Hirschsprung Disease

Griseri, Paola; Pesce, Bárbara; Patrone, Giovanna; Osinga, Jan; Puppo, Francesca; Sancandi, Monica; Hofstra, Robert; Romeo, Giovanni; Ravazzolo, Roberto; Devoto, Marcella; Ceccherini, Isabella

doi:10.1086/342774

Cited by 38 publications

(42 citation statements)

References 16 publications

(13 reference statements)

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“…In the current series a variant allele of RET exon 14; S836S (c2508C > T) was detected that has been found in no other Asian series (Garcia-Barcelo et al 2003;Wu et al 2005;Sakai et al 2000) and was detected in reduced frequency compared with healthy subjects in Italian HSCR (Griseri et al 2000(Griseri et al , 2002. In our HSCR, the minor allele in this polymorphism was found exclusively in patients of Malay-Thai extraction who had LSD.…”

Section: Discussionsupporting

confidence: 53%

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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Section: Discussionsupporting

confidence: 53%

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

et al. 2006

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“…Several association and haplotype studies also support this hypothesis. 26,32,33 Conserved haplotypes could be constructed using the alleles identified for different markers in and around the RET gene. 24,34 -36 Carrasquilo et al 34 used the highest number of SNPs in and around the RET locus.…”

Section: Discussionmentioning

confidence: 99%

“…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). 26 Of the four microsatellite markers, two were located upstream of RET, namely D10S1100 27 (300 kb upstream) and M353 28 (80 kb upstream), one located within intron 5, MRETint5, 28 and one is located 38 kb downstream the RET gene, s-TCL2 28 ( Figure 1).…”

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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“…Functional analyses of M1064 failed to demonstrate significant changes in the activity of RET (31 ), and experiments in transgenic mice indicated that RET51 is not required for the development of the ENS (40 ). However, based on the demonstration of the formation of homoand heterodimers between RET9 and RET51, it has recently been suggested that there may be a critical role for the RET51:RET9 ratio in addition to that of the absolute amounts of the two isoforms (41 ).…”

Section: Sequence Alterations In Ret and Gdnfmentioning

confidence: 99%

Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

Garcia-Barceló

Sham²,

Lee

et al. 2004

Clinical Chemistry

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Background: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract.HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system. Methods: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls. Results: We identified 10 novel and 2 previously described mutations in RET, and 4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential diseasecausing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males (P ‫؍‬ 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB,

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A Rare Haplotype of the RET Proto-Oncogene Is a Risk-Modifying Allele in Hirschsprung Disease

Cited by 38 publications

References 16 publications

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

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

Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

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