RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease

Borrego, Salud; Ruiz, Agustı́n; Sáez, María Eugenia; Gimm, Oliver; Gào, Xīn; López-Alonso, Manuel; Hernández, Antonio F.; Wright, Fred A.; Antiñolo, Guillermo; Eng, Charis

doi:10.1136/jmg.37.8.572

Cited by 96 publications

(70 citation statements)

References 31 publications

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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%

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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Section: Discussionmentioning

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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“…It is puzzling that, while the allelic distribution in INDB and the controls is not statistically different, the genotypic distribution at this locus shows a trend to significance of p=0.01. From previous analyses, we know that L769L and the coding haplotypes of which it is comprised were also overrepresented in our series of HSCR patients in comparison with the normal population (11,12). A detailed examination of the raw data reveals that such significance is due to an excess of homozygous individuals for the G allele in cases versus controls.…”

Section: Discussionmentioning

confidence: 96%

“…construct haplotypes comprising the three cSNPs as previously described (haplotypes A to L) (12). No significant differences were observed after comparing the general haplotypic distribution of INDB patients and controls (¯2=7.28 with six degrees of freedom, p=0.29554021) or HSCR+INDB patients and isolated HSCR (¯2=4.70 with six degrees of freedom, p=0.58278287).…”

Section: Variant Indb Vs Hscr+indb (%) Indb Vs Hscr (%) Indb Vs Comentioning

confidence: 99%

“…Selection of the variants was based on their previously reported association with either HSCR or another disease, such as sporadic medullary thyroid cancer, papillary thyroid cancer or pheochromocytoma (5)(6)(7)(11)(12)(13)(14). Large scale genotyping of all these RET SNPs was performed using TaqMan-based techniques for allelic discrimination (TaqMan ® SNP Genotyping Assay, Applied Biosystems, Foster City, CA) according to the manufacturer's recommendations.…”

Section: Selection and Genotyping Of Ret Sequence Variantsmentioning

confidence: 99%

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Is the RET proto-oncogene involved in the pathogenesis of intestinal neuronal dysplasia type B?

Fernández

Sánchez-Mejías²,

Ruiz-Ferrer³

et al. 2009

Mol Med Rep

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Abstract. Hirschsprung disease (HSCR) is defined by the absence of intramural ganglia of Meissner and Auerbach along variable lengths of the gastrointestinal tract. Intestinal neuronal dysplasia (IND) type B is characterized by the malformation of the parasympathetic submucous plexus of the gut. A connection appears to exist between these two enteric nervous system abnormalities. Due to the major role played by the RET proto-oncogene in HSCR, we sought to determine whether this gene was also related to INDB. dHPLC techniques were employed to screen the RET coding region in 23 patients presenting with INDB and 30 patients with a combined HSCR+INDB phenotype. In addition, eight RET single nucleotide polymorphisms (SNPs) were strategically selected and genotyped by TaqMan technology. The distribution of SNPs and haplotypes was compared among the different groups of patients (INDB, HSCR+INDB, HSCR) and the controls. We found several RET mutations in our patients and some differences in the distribution of the RET SNPs among the groups of study. Our results suggest an involvement of RET in the pathogenesis of intestinal INDB, although by different molecular mechanisms than those leading to HSCR. Further investigation is warranted to elucidate these precise mechanisms and to clarify the genetic nature of INDB.

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“…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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RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease

Abstract: Background-Hirschsprung disease (HSCR),

Cited by 96 publications

References 31 publications

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

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

Is the RET proto-oncogene involved in the pathogenesis of intestinal neuronal dysplasia type B?

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

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