Characterization of a rare mosaic X-ring chromosome in a patient with Turner syndrome.

BACKGROUND: Ring chromosomes can be formed by terminal breaks of two arms of a chromosome and their rejoining, leading to a loss of genetic material. They may also be formed by telomere-telomere fusions with no deletion, resulting in the formation of a complete ring. Mosaic X-ring chromosomes are extremely rare and have highly variable phenotypes. Here, we report a case with a mosaic X-ring chromosome in a patient with Turner syndrome, and we illustrate the unreported complicated mechanism using chromosome analysis and fluorescence in situ hybridization (FISH). CASE PRESENTATION: A 10-year-old girl of short stature presenting Turner syndrome was admitted to our hospital. The patient's clinical characteristics were subsequently documented. Genetic analysis showed a karyotype of mostly 45,X[140]/46,X,r(X)[60]. The X ring chromosome was cytogenetically characterized as 45,X/46,X,r(X)(p22.32q21.1), with a length of approximately 74 Mb. CONCLUSIONS: Taken together, we report a rare case with a mosaic X ring chromosome in Turner syndrome and we believe this case expands our collective knowledge of mosaic structural chromosomal disorders and provides new insight into clinical management and genetic counseling for Turner syndrome.

[Analysis of NRXN1 gene deletion in an autistic patient].

OBJECTIVE: To explore the genetic basis for a patient with autism. METHODS: High-throughput sequencing was carried out to detect copy number variations in the patient. RESULTS: DNA sequencing found that the patient has carried a 0.11 Mb deletion in distal 2p16.3 spanning from genomic position 50 820 001 to 50 922 000, which resulted removal of exon 6 and part of intron 7 of the NRXN1 gene. The same deletion was not found his parents and brother. CONCLUSION: Partial deletion of the NRXN1 gene may underlie the disease in this patient.

Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease.

CITED2 gene is an important cardiac transcription factor that plays a fundamental role in the formation and development of embryonic cardiovascular. Previous studies have showed that knock-out of CITED2 in mice might result in various cardiac malformations. However, the mechanisms of CITED2 mutation on congenital heart disease (CHD) in Chinese Tibetan population are still poorly understood. In the present study, 187 unrelated Tibetan patients with CHD and 200 unrelated Tibetan healthy controls were screened for variants in the CITED2 gene; we subsequently identified one potential disease-causing mutation p.G143A in a 6-year-old girl with PDA and functional analyses of the mutation were carried out. Our study showed that the novel mutation of CITED2 significantly enhanced the expression activity of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia inducible factor 1-aipha (HIF-1A), which is closely related with embryonic cardiac development. As a result, CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease.

Variations of CITED2 are associated with congenital heart disease (CHD) in Chinese population.

CITED2 was identified as a cardiac transcription factor which is essential to the heart development. Cited2-deficient mice showed cardiac malformations, adrenal agenesis and neural crest defects. To explore the potential impact of mutations in CITED2 on congenital heart disease (CHD) in humans, we screened the coding region of CITED2 in a total of 700 Chinese people with congenital heart disease and 250 healthy individuals as controls. We found five potential disease-causing mutations, p.P140S, p.S183L, p.S196G, p.Ser161delAGC and p. Ser192_Gly193delAGCGGC. Two mammalian two-hybrid assays showed that the last four mutations significantly affected the interaction between p300CH1 and CITED2 or HIF1A. Further studies showed that four CITED2 mutations recovered the promoter activity of VEGF by decreasing its competitiveness with HIF1A for binding to p300CH1 and three mutations decreased the consociation of TFAP2C and CITED2 in the transactivation of PITX2C. Both VEGF and PITX2C play very important roles in cardiac development. In conclusion, we demonstrated that CITED2 has a potential causative impact on congenital heart disease.

Quercetin is able to demethylate the p16INK4a gene promoter.

BACKGROUND: Quercetin is a flavonoid found ubiquitously in nature. Studies in vitro and in vivo have suggested that quercetin may have a protective role against colon cancer. METHODS: We selected the human colon cancer cell line RKO to investigate the effects of quercetin in vitro. RKO cells were treated with different concentrations of quercetin. RESULTS: In comparison to the control, quercetin was able to inhibit the growth of RKO cells, as measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Untreated RKO cells demonstrated almost complete methylation of the p16INK4a gene. Hypermethylation of the p16INK4a gene was successfully reversed after 120 h of treatment with quercetin. Expression of the p16INK4a gene was restored in a concentration-dependent manner. CONCLUSION: All these data suggest that quercetin has antitumor properties, probably via demethylation of the p16INK4a gene promoter.

Nordihydroguaiaretic acid restores expression of silenced E-cadherin gene in human breast cancer cell lines and xenografts.

In our study we use nordihydroguaiaretic acid (NDGA), the naturally occurring lignan, to investigate whether it plays a role in the prevention and treatment of cancer by epigenetic modifications. The growth inhibitory effect of NDGA on human breast cancer cell lines was determined using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay). It substantially inhibited the growth of human breast cancer cell lines SKBR3 and MDA-MB-435 with an estimated IC50 of 31.09+/-1.6 and 38.8+/-2.1 micromol/l respectively, after 4 days incubation with different NDGA concentrations. The in-vivo anticancer activity of NDGA was evaluated by calculating the tumor growth inhibition value. NDGA substantially inhibited the growth of human breast carcinoma cells in both animal and cell-based models. We also found that a single treatment with NDGA reactivates methylation-silenced E-cadherin gene in vitro and in vivo, suggesting an intriguing concept that lignans may act as natural effective epigenetic modifiers in the prevention and treatment of cancer.

The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer's disease in Chinese.

A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in East Asian. A case-control study from Japan found that ALDH2*2 was associated with late-onset AD (LOAD), interacting synergistically with the presence of the apolipoprotein E allele 4 (APOE epsilon4). But the subsequent studies in Koreans didn't find the similar result. To determine whether the ALDH2 gene 1/2 polymorphism contributes to the risk for LOAD in Chinese, we have investigated 188 sporadic LOAD patients and 223 healthy controls from Chinese. A significantly increased risk of AD in the carriers of ALDH2*2 allele (OR=3.11, 95% CI 2.06-4.69, P<0.001) was observed. After stratifying by APOE epsilon4 status, increased LOAD risks associated with the ALDH2 2 allele carriers only in the APOE epsilon4 non-carriers (chi2=31.79, df=1, P<0.001) and with the 2-allele in either groups (chi2=6.64 df=1, P=0.0099 and chi2=37.38, df=1, P<0.001) were seen. These results suggested that the ALDH2 gene 1/2 polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese.

Association between Alzheimer's disease and the NOS3 gene Glu298Asp polymorphism in Chinese.

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer's disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (chi2 = 9.12, df = 1, P = 0.003 by genotype; chi2 = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon 4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE epsilon 4 noncarriers (chi2 = 6.28, df = 1, P = 0.012 by genotype; chi2 = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE epsilon 4 status in Chinese.

Reactivation of methylation-silenced tumor suppressor gene p16INK4a by nordihydroguaiaretic acid and its implication in G1 cell cycle arrest.

Phytoestrogens, including the two major groups isoflavones and lignans, are chemicals with weak estrogenic activity which occur naturally in many foods and herbs. Recently, several intriguing studies reported that some isoflavones can affect DNA methylation status. However, little is known about the effect of plant lignans on epigenetic modification. Using cultured T47D and RKO human cancer cells as a model, we studied the modulating effects of nordihydroguaiaretic acid (NDGA), a member of the lignan family, on the methylation status of the gene promoter region. Our results indicated that NDGA reverses p16INK4a CpG island hypermethylation, and restores its transcription and expression in both cell lines. Cytometric analysis showed that NDGA significantly affects cell cycle progression by arresting cells at the G1 phase. Consistent with the reacquisition of p16INK4a expression, we also found that NDGA induces cellular senescence in cancer cells. This is the first study demonstrating that a member of the lignan family can induce demethylation in human cancer cell lines, suggesting a novel epigenetic mechanism in the prevention or treatment of cancer.