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, Mercè; Sham, Mai Har; Lee, Wing‐Shan; Lui, Vincent Chi-Hang; Chen, Benedict Ling-Sze; Wong, Kenneth K.; Wong, Janus Siu Him; Tam, Paul Kwong‐Hang

doi:10.1373/clinchem.2003.022061

Cited by 54 publications

(48 citation statements)

References 44 publications

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“…Homozygotes of both the A allele of c135 G>A (A45A) and G allele of c2307T>G (L769L) was the most frequent genotype in HSCR patients (36%) while heterozygotes of both polymorphic sites were most common in controls (36%). The results were similar with the Hong-Kong studies (Garcia-Barcelo et al 2004) but different with the Caucasian populations (Borrego et al 1999;Fitze et al 1999). Furthermore, all but two of the LSA/TCA patients were homozygous for allele A of c135G>A and allele G of c2307T>G (82%).…”

Section: Ret Genotypessupporting

confidence: 84%

“…The RET mutation rate in our HSCR patients seems to be low compared with those reported in other populations. In general, studies on sporadic HSCR yield lower frequencies of RET mutation studies than the familial cases (7-20% compared with 50%; Angrist et al 1995;Edery et al 1994;Garcia-Barcelo et al 2004;Garcia-Barcelo et al 2003;Romeo et al 1994;Sakai et al 2000;Seri et al 1997;Svensson et al 1998). However, germline RET mutation is associated with only 3% of a population-based series of isolated HSCR (Svensson et al 1998).…”

Section: Discussionmentioning

confidence: 98%

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Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Tsai

Chu

et al. 2005

J Hum Genet

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Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/ GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.

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Section: Ret Genotypessupporting

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Tsai

Chu

et al. 2005

J Hum Genet

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“…To our knowledge, this is the first study that has used a fluorescence-based SNP detection assay for genotyping RET-protooncogene and NRG1, as previous studies have usually used PCR-direct sequencing, single-stranded conformation polymorphisms and restriction fragment length polymorphisms. 5,13,14,16,20,21 This fluorescence-based technique relies on different properties of two probes that are specific to the alleles of interest, each labeled with different fluorescent markers. It offers several advantages compared with older techniques; not only does it feature high specificity and accuracy, but also not requiring a post-amplification step reduces the time and cost of genotyping.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] Recent studies have suggested the RET-protooncogene as a major locus involved in HSCR pathogenesis. [11][12][13] Single-nucleotide polymorphisms (SNPs) of the RET-protooncogene have been demonstrated to have an association with HSCR in various studies in Asians, [12][13][14][15][16] the majority of these studies were conducted in East Asian populations.…”

Section: Introductionmentioning

confidence: 99%

Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients

et al. 2012

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Hirschsprung disease (HSCR) is a congenital developmental defect of the enteric nervous system known to be associated with the RET-protooncogene and other candidates. Recently, a genome-wide association study has added NRG1, a regulator of the development of the enteric ganglia precursors, as a new candidate gene. The aim of this study is to validate the association of the RET-protooncogene and the NRG1 in HSCR in Thai patients. The study used TaqMan single-nucleotide polymorphism (SNP) genotyping and PCR-restriction fragment length polymorphism for genotyping of 10 SNPs within the RET-protooncogene and four SNPs within the NRG1, in 68 Thai sporadic HSCR cases and 120 ethnic-matched controls. On univariate disease association analysis, 9 of 10 RET-protooncogene SNPs and all four NRG1 SNPs showed an association with HSCR. The rs2435357 (RET-protooncogene) and rs2439305 (NRG1) showed the strongest associations with the disease at P-values of 8.17E-09 (odds ratio (OR)¼6.43, 95% confidence intervals (CI)¼3.33-12.40) and 6.94E-03 (OR¼3.28, 95% CI¼1.28-8.38), respectively. The RET-protooncogene rs2435357 (TT genotype) in combination with the NRG1 rs2439305 (GG genotype) was strongly associated with an increased risk of HSCR with a P-value of 1.99E-04 (OR¼20.34, 95% CI; 2.54-162.78) when compared with a single SNP of the RET-protooncogene or NRG1. Genetic variation of the RET-protooncogene and NRG1 is involved in the risk of HSCR development in the Thai population. Moreover, the study also detected a combined effect of SNPs by SNP-SNP interaction, which may help in predicting HSCR risk.

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“…The mutation rate of RET among Asians is from 3.6 to 24% (Wu et al 2005;Sakai et al 2000;Tou et al 2006;Garcia-Barcelo et al 2004). Considering missense mutations in sporadic HSCR alone, figures reported are 7.1% for the Japanese (Sakai et al 2000), 24% for Hong Kong Chinese , and 0% for Taiwan Chinese (Wu et al 2005).…”

Section: Discussionmentioning

confidence: 97%

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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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

Cited by 54 publications

References 44 publications

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan

Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients

Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients

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