Chinese patients with sporadic Hirschsprung's disease are predominantly represented by a single RET haplotype.

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Role of RET and PHOX2B gene polymorphisms in risk of Hirschsprung's disease in Chinese population [9]

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Hedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway- based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR.published_or_final_versio

Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

Background: The BRCA1 gene is an important breast-cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease. Methods and Results: Using direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T→C (rs799908:T→C), c.-2265C→T (rs11655505:C→T), c.-2004A→G (rs799906:A→G) and c.-1896(ACA) 1→(ACA) 2 (rs8176071:(ACA) 1→(ACA) 2) present in Hong Kong Chinese. Each polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had stronger binding than the C allele, and the most common mutant haplotype, which contains the c.-2265T allele, increased promoter activity by 70%. Risk association first tested in Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% Cl 0.69 to 0.93; p = 0.003) which was more evident among women aged ≥45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% Cl 0.61 to 0.91; p = 0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged ≥45 years without a family history of breast cancer (OR = 0.64, 95% Cl 0.46 to 0.89; p = 0.008). Conclusion: This comprehensive study of BRCA1 promoter polymorphisms found four variants that altered promoter activity and with the most significant contribution from c.-2265C→T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.published_or_final_versio

Lack of association between nNOS -84G>A polymorphism and risk of infantile hypertrophic pyloric stenosis in a Chinese population

Background: Infantile hypertrophic pyloric stenosis (IHPS) is one of the most common gastrointestinal obstructions in the infancy requiring surgery. Reduced expression of neuronal nitric oxide synthase (nNOS), which plays an important role in the regulation of the human pyloric muscle, is thought to underlie IHPS. The role of nNOS in IHPS has been supported by the genetic association of a functional regulatory nNOS polymorphism (-84G>A) with IHPS in whites. We reasoned that the corroboration of this association in a population of different ethnic origin would prompt follow-up studies and further investigation of the IHPS pathology at molecular level. Thus, we attempted to reproduce the original findings in a Chinese population of comparable size in what would be the first genetic study on IHPS conducted in Chinese. Methods: nNOS -84G>A genotypes were analyzed in 56 patients and 86 controls by polymerase chain reaction and DNA sequencing. Logistic regression was used to compute odds ratios. Results: Our study could not corroborate the association previously reported. Although the frequency of the IHPS-associated allele (-84A) in controls (0.205) was similar to that reported for white controls, there was a dramatic difference in -84A frequencies between white and Chinese patients (0.198). Similarly, there was no difference in the nNOS -84G>A genotype distribution between patients and controls, even when the GA and AA genotypes were combined to compare GG genotype (odds ratio, 1.01; 95% confidence interval, 0.47-2.19). Conclusions: Failure to replicate the initial finding does not detract from its validity, because genetic effects may differ across populations. Differences across populations in linkage disequilibrium and/or allele frequencies may contribute to this lack of replication. The role nNOS in IHPS awaits further investigation. © 2010 Elsevier Inc. All rights reserved.postprin

Dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients

Epidemiological studies have shown a lower prevalence of tardive dyskinesia (TD) among Chinese psychiatric patients compared to Caucasian and Black patient populations. It has been hypothesized that pharmacogenetic factors may underlie this cross-cultural difference. Due to the important implications of the dopamine D3 receptor gene (DRD3) in motor control, we investigated the frequency of polymorphic serine (ser) to glycine (gly) substitution of the gene DRD3 in Chinese schizophrenic patients. The sample size consisted of 65 patients with TD and 66 without TD. Patients were assessed for the severity of TD, the presence of akathisia and parkinsonian symptoms and were subsequently genotyped. We found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia in Chinese patients with schizophrenia.link_to_subscribed_fulltex

Is there a role for the IHH gene in Hirschsprung's disease?

Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells along a variable length of the intestine. HSCR has a complex genetic aetiology with 50% of the patients unexplained by mutations in the major HSCR genes. The Ihh gene is involved in the development of the enteric nervous system (ENS) and Ihh mutant mice present with a phenotype reminiscent of HSCR. The requirement of Ihh signalling for the proper development of the ENS, together with the evidence presented by the Ihh murine model, prompted us to investigate the involvement of the human IHH gene in HSCR. Sequence analysis revealed seven single nucleotide polymorphisms, six of which were new. Allele and haplotype frequencies were compared between cases and controls, and, among the cases, between genders, between different phenotypes, and between patients with different mutation status in the main HSCR genes. Despite the involvement of IHH in the development of the ENS, IHH is not a major gene in HSCR. Nevertheless, as the manifestation of the HSCR phenotype is genetic background dependent, polymorphic loci should be tested simultaneously to characterize gene-gene interaction. The involvement of IHH in other intestinal anomalies should be investigated.link_to_subscribed_fulltex

Radiation hybrid mapping of human cytosolic malate dehydrogenase (hcMDH) to the short arm of chromosome 2

Compartmentalization of human cytosolic malate dehydrogenase, hcMDH, together with its isozyme partner-mitochondrial form, hmMDH, plays an important role in the aerobic metabolism of the malate-aspartate shuttle and the citric acid cycle. However, they share few structural homology at the molecular level. The pseudogenes of mMDH has been reported in mice but hcMDH has no pseudogenes as shown by Southern blot analysis. A single band only was detected for the EcoRI digestion with 9.4 kb long of human genomic DNA and HindIII cutting with 2.8kb long. hcMDH gene was mapped to chromosome 2 by somatic cell hybrid analysis and further localised to 268.72cR from the top telomere of Chromosome 2 (near 2p15) by radiation hybrid mapping. The genes falling into this region may be related to dilated cardiomyopathy (DCM), several types of cancers and immunoregulation mechanism of cancers.link_to_subscribed_fulltex

MNX1 (HLXB9) mutations in Currarino patients

Purpose: The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in MNX1 motor neuron and pancreas homeobox 1 (previously HLXB9). Here, we report on the MNX1 mutations found in a family segregating CS and in 3 sporadic CS patients, as well as on the clinical characteristics of the affected individuals. Methods: MNX1 mutations were identified by direct sequencing the coding regions, intron/exon boundaries of MNX1 in 5 CS Japanese family members and 3 Chinese sporadic cases and their parents. Results: There were 2 novel (P18PfsX37, R243W) and 2 previously described (W288G and IVS2 + 1G > A) mutations. These mutations were not found in 198 control individuals and are predicted to impair the functioning of the MNX1 protein. Conclusions: The variability of the CS phenotype among related or unrelated patients bearing the same mutation advocates for differences in the genetic background of each individual and invokes the implication of additional CS susceptibility genes. © 2009 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus

Hirschsprung's disease (HSCR, colonic aganglionosis) is an oligogenic entity that usually requires mutations in RET and other interacting loci. Decreased levels of RET expression may lead to the manifestation of HSCR. We previously showed that RET transcription was decreased due to alteration of the TITF1 binding site by two HSCR-associated RET promoter single nucleotide polymorphisms (SNPs). This prompted us to investigate whether DNA alterations in TITF1 could play a role in HSCR by affecting the RET - regulatory properties of the TITF1 protein. Our initial study on 86 Chinese HSCR patients revealed a Gly322Ser amino acid substitution in the TITF1protein. In this study we have examined an additional 102 Chinese and 70 Caucasian patients, and 194 Chinese and 60 Caucasian unselected, unrelated, subjects as controls. The relevance of the DNA changes detected in TITF1 by direct sequencing were evaluated using bioinformatics, reporter and binding-assays, mouse neurosphere culture, immunohistochemistry and immunofluorescence techniques. Met3Leu and Pro48Pro were identified in 2 Caucasian patients and 1 Chinese patient, respectively. In vitro analysis showed that Met3Leu reduced the activity of the RET promoter by 100% in the presence of the wild-type or HSCR-associated RET promoter SNP alleles. The apparent binding affinity of the TITF1 mutated protein was not decreased. The Met3Leu mutation may affect the interaction of TITF1 with its protein partners. The absence of Titf1 expression in mouse gut but not in human gut suggests that the role of TITF1 in gut development differs between the two species. TITF1 mutations could contribute to HSCR by affecting RET expression through defective interactions with other transcription factors. © 2007 The Authors Journal compilation © 2007 University College London.link_to_OA_fulltex