Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing

Objective: To evaluate the impact of genetic testing in the management of familial multiple endocrine neoplasia 2A patients. Design: Retrospective study. Setting: University teaching hospital, Hong Kong. Patients: Twenty-two patients from eight multiple endocrine neoplasia 2A families underwent prophylactic total thyroidectomy based on a positive RET mutation genetic testing. All mutations were located at codon 634 of exon 11. Nineteen patients had preoperative basal serum calcitonin measured, and the 12 with normal levels had pentagastrin stimulation tests. Preoperative thyroid ultrasound examination was performed for 17 patients. Results: There were 13 females and 9 males with a median age of 25.1 (range, 6.1-71.9) years. Histopathology revealed medullary thyroid carcinoma in 17 (77%), C-cell hyperplasia in four (18%), and normal pathology in one (5%) of the patients. Five patients with either C-cell hyperplasia or normal pathology were among the youngest (age range, 6-9 years). The youngest patient with medullary thyroid carcinoma was nearly 9 years old. The median size of medullary thyroid carcinomas was 8.3 (range, 0.1-18) mm, but there were no lymph node metastases. Of 15 patients with normal basal calcitonin levels, 10 had medullary thyroid carcinoma, though two tested negative with the pentagastrinstimulated calcitonin assay. Five of six patients with normal preoperative ultrasonographic examinations had medullary thyroid carcinoma. Three (14%) of the patients were prescribed long-term calcium and vitamin D supplementation. After a median follow-up of 49 (range, 13-128) months, no patient had recurrence of medullary thyroid carcinoma. Conclusions: Genetic testing has replaced conventional biochemical and radiological modalities to identifying multiple endocrine neoplasia 2A carriers, in order to offer them prophylactic thyroidectomy. Chinese multiple endocrine neoplasia 2A patients with codon 634 mutation seem to have less aggressive forms of medullary thyroid carcinoma, for whom prophylactic thyroidectomy can be considered at the age of 8 years.published_or_final_versio

Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3

Background: The rearranged during transfection (RET) gene encodes a single-pass receptor whose proper expression and function are essential for the development of enteric nervous system. Mutations in RET regulatory regions are also associated with Hirschsprung disease (HSCR) (aganglionosis of the colon). We previously showed that 2 polymorphisms in RET promoter are associated with the increased risk of HSCR. These single nucleotide polymorphisms overlap with the NK2 homeobox 1 (Nkx2-1) binding motif interrupting the physical interaction of NKX2-1 with the RET promoter and result in reduced RET transcription. In this study, we further delineated Nkx2-1-mediated RET Transcription. Methods and results: First, we demonstrated that PHOX2B, like SOX10 and NKX2-1, is expressed in the mature enteric ganglions of human gut by immunohistochemistry. Second, subsequent dual-luciferase-reporter studies indicated that Nkx2-1 indeed works coordinately with Phox2b and Sox10, but not Pax3, to mediate RET transcription. In addition, identification of Phox2b responsive region in RET promoter further provides solid evidence of the potential functional interaction between Phox2b and RET. Conclusion: In sum, Phox2b and Sox10 act together with Nkx2.1 to modify RET signaling and this interaction may also contribute to HSCR susceptibility. © 2009 Elsevier Inc. All rights reserved.postprin

SMYD3 tandem repeats polymorphism is not associated with the occurrence and metastasis of hepatocellular carcinoma in a Chinese population

A variable number of tandem repeats (VNTR) polymorphism in regulatory region of SMYD3 coding for histone methyltransferase has been shown to be associated with colorectal cancer, hepatocellular carcinoma (HCC), and breast cancer in Japanese population. Aim of the study is to investigate the potential association between the functional SMYD3 tandem repeats polymorphism and HCC in Chinese population. Material and Methods: The case-control study included 200 HCC patients and 261 healthy controls. The VNTR polymorphism in the promoter of SMDY3 was genotyped by PCR and direct-sequencing analysis. Odds ratio and 95% confidence interval were used to estimate the association between the polymorphisms and risk of HCC. Results: The allele frequencies for SMYD3 2 and 3 repeats were 15.71% and 84.29% among controls; and 12.75%, and 87.25% among cases (P = 0.22). The odds ratio for 3/3 versus 2/2 and 2/3 genotypes was 1.30 (P = 0.18). The frequencies of 3 alleles were not increased with HCC stage increased (trend test, P = 0.45). Conclusion: SMYD3 polymorphism is not associated with the occurrence and metastasis of HCC in Chinese population. Copyright © Experimental Oncology, 2007.link_to_subscribed_fulltex

Genetic analysis of CYP2D6 locus of Hong Kong Chinese psychiatric patients

The genetically determined polymorphism of debrisoquine hydroxylase (cytochrome P4502D6, CYP2D6) shows marked interethnic differences due to the different distribution of the alleles of the CYP2D6 gene in different populations. Differences are not only in the incidence of poor metabolizers (PM) of debrisoquone, but also in the enzyme activity within the extensive metabolizer (EM) phenotype. The distribution of the debrisoquine metabolic ratios (MR) is shifted towards higher values among Oriental EMs compared to Caucasian EMs due to the high prevalence of the CYP2D6*10 allele [nomenclature according to Daly et al., 1996] in this population [Wang et al., 1993]. The prevalence of the different alleles of the CYP2D6 gene may be different within different Oriental populations or in particular patient groups. The genotype of 54 patients with diagnosis of major depression according to DSM IV was assessed for the prevalence of the alleles CYP2D6*10, CYP2D6*4, and CYP2D6*8 (the prevalence of which in Chinese is not known). Mutation 2938C→T indicative of CYP2D6*2 (allele L) was also assessed in five patients homozygous for CYP2D6*10 and was found to be absent. Genotyping was performed according to published methods. The CYP2D6*8 and CYP2D6*4 alleles were absent in the present population studied as expected. The CYP2D6*10 allele frequency was 0.6 in the present study, similar to that found among Singaporean Chinese, higher than that found among the Japanese, Koreans, and Chinese living in Sweden (0.51), and lower than that among Taiwanese (0.7) [Wang et al., 1993; Yokota et al., 1993; Lee and Jeyaseelan, 1994; Roh et al., 1996]. Genotyping a healthy Hong Kong Chinese population and testing for other variants of the CYP2D6 gene is in progress. This is the first CYP2D6 genotyping study conducted on a Hong Kong Chinese population. It will contribute to previous data on differences among EMs of different Oriental origins.link_to_subscribed_fulltex

Deletion of interleukin enhancer binding factor 2 (ILF2) resulted in defective biliary development and bile flow blockage

202010 bcmaVersion of RecordPublishe

Prokineticin-1 (Prok-1) works coordinately with glial cell line-derived neurotrophic factor (GDNF) to mediate proliferation and differentiation of enteric neural crest cells

Enteric neural crest cells (NCC) are multipotent progenitors which give rise to neurons and glia of the enteric nervous system (ENS) during fetal development. Glial cell line-derived neurotrophic factor (GDNF)/RET receptor tyrosine kinase (Ret) signaling is indispensable for their survival, migration and differentiation. Using microarray analysis and isolated NCCs, we found that 45 genes were differentially expressed after GDNF treatment (16 h), 29 of them were up-regulated including 8 previously undescribed genes. Prokineticin receptor 1 (PK-R1), a receptor for Prokineticins (Prok), was identified in our screen and shown to be consistently up-regulated by GDNF in enteric NCCs. Further, PK-R1 was persistently expressed at a lower level in the enteric ganglions of the c-Ret deficient mice when compared to that of the wild-type littermates. Subsequent functional analysis showed that GDNF potentiated the proliferative and differentiation effects of Prok-1 by up-regulating PK-R1 expression in enteric NCCs. In addition, expression analysis and gene knock-down experiments indicated that Prok-1 and GDNF signalings shared some common downstream targets. More importantly, Prok-1 could induce both proliferation and expression of differentiation markers of c-Ret deficient NCCs, suggesting that Prok-1 may also provide a complementary pathway to GDNF signaling. Taken together, these findings provide evidence that Prok-1 crosstalks with GDNF/Ret signaling and probably provides an additional layer of signaling refinement to maintain proliferation and differentiation of enteric NCCs. © 2007 Elsevier B.V. All rights reserved.link_to_subscribed_fulltex

Novel RET mutation produces a truncated RET receptor lacking the intracellular signaling domain in a 3-generation family with Hirschsprung disease

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Mutations in the NRG1 gene are associated with Hirschsprung disease

Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1. © 2011 Springer-Verlag.link_to_subscribed_fulltex