Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency.

OBJECTIVE: To explore the candidate pathogenic gene in a premature ovarian insufficiency (POI) proband from a consanguineous marriage and detect the potential effects of mutation on cellular energy metabolism. DESIGN: Genetic and functional studies. SETTING: Reproductive medicine center. PATIENT(S): A patient with POI, from a consanguineous family, and her family members were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University. INTERVENTION(S): Whole exome sequencing (WES) was performed for the proband. Variation revealed by WES sequencing was validated by Sanger sequencing in her family. Sequencing data were combined with those of other sporadic cases listed in public databases to identify the causative gene. MAIN OUTCOME MEASURE(S): Rare homozygous nonsynonymous variants were identified and included in subsequent analysis. Metabolic analyzes were performed using Seahorse XFe96 analyzers to measure oxygen consumption and then obtain further results of ATP production and extracellular acidification rate. The differences in energy metabolism measurements between wild type and mutation were analyzed and compared. RESULT(S): A novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation (NM_020745: exon2: c.337G>C: p. G113R) was identified in the aminoacylation region using WES. The mutation was highly conserved among species and predicted to be disease causing. AARS2 encodes mitochondrial alanyl-tRNA synthetase, which attaches alanine onto tRNA-ala. AARS2 mutations were previously reported in female leukodystrophy patients with POI. In mitochondrial stress tests, the ATP productions of the mutation group (3.58 ± 0.46 fmol/min/cell) was significantly lower than that of the wild type group (6.96 ± 1.56 fmol/min/cell). CONCLUSION(S): This is the first report of a homozygous pathogenic AARS2 mutation in POI. This mutation may lead to incorrect aminoacylation of tRNA, affect mitochondrial translation, and cause oxidative phosphorylation defects, which may be responsible for POI.

TNFRSF21 mutations cause high myopia.

BACKGROUND: High myopia (HM) is one of the leading causes of vision impairment worldwide, accompanied by a series of pathological ocular complications. Studies have shown that genetic factors play an important role in the pathogenesis of HM. The aim of our study is to identify a candidate gene for a large family with non-syndromic HM. METHODS: A large Chinese family, including 12 patients with non-syndromic HM, and 220 unrelated patients with HM, were recruited from the Department of Ophthalmology, Peking Union Medical College Hospital. Three affected subjects from the large family were selected to perform whole exome sequencing (WES). Rare heterozygous variants shared by all three subjects were retained and then Sanger sequencing was used to determine whether any of the remaining variants cosegregated with the disease phenotype. Furthermore, all coding regions of the candidate genes were analysed in 220 unrelated patients with HM. Immunofluorescence assay was used to detect the expression of the candidate gene in the eye. Annexin V/PI staining and flow cytometry were applied to detect cell apoptotic changes. RESULTS: WES identified a novel TNF receptor superfamily member 21 (TNFRSF21) variant, P146A, in a large Chinese family with HM, and another three rare heterozygous variants (P202L, E240* and A440G) in TNFRSF21 were found in 220 unrelated cases with HM. Immunofluorescence assay indicated that it is strongly expressed in the mouse eye. Compared with the wild type, the P146A variant could significantly increase adult retinal pigment epithelial cell line-19 cell apoptotic levels. CONCLUSIONS: Variants in TNFRSF21 cause non-syndromic HM in Chinese population.

CAPS Mutations Are Potentially Associated with Unexplained Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is a major concern for women's reproductive health. Several studies have proved that genetics is a major factor leading to unexplained RPL, but the maternal pathogenic genes involved in RPL remain largely unknown. A consanguineous family, including the parents who were cousins and their three daughters who had been diagnosed as having nonsyndromic unexplained RPL, was recruited in this study. A rare homozygous variant in calcyphosine (CAPS; ENST00000588776: c.377delC, p.Leu127Trpfs) might be the potential candidate variant for this RPL family through whole-exome sequencing. Sanger sequencing confirmed that the three affected sisters carried the homozygous p.Leu127Trpfs, whereas their parents carried the heterozygous p.Leu127Trpfs. CAPS encodes a Ca2+-binding protein and may play a role in the regulation of Ca2+ transport. Although the precise underlying mechanisms remain unclear, the previous study suggested that they may be involved in cross talk between Ca2+ signaling and cAMP-protein kinase A pathways, which are crucial to embryo implantation and pregnancy maintenance. Knockdown of CAPS expression might promote the expression of secreted phosphoprotein 1 and matrix metalloproteinase 9, and the release of prostaglandin E2, which all played important roles in embryo implantation and early pregnancy maintenance. These results indicated that the autosomal recessive homozygous mutation, p.Leu127Trpfs, in CAPS might be a maternal effect causative mutation of RPL pathogenesis.

Carrying the T Allele of the SNP rs574344, an eQTL of GSTM1, Contributes to Longevity in the Han Chinese Population.

BACKGROUND: There has been recent recognition that the GSTM1 gene is associated with successful aging and longevity. It has been hypothesized that individuals with a GSTM1 deletion are at a greater risk for developing a plethora of diseases. This study was carried out to investigate the association between the rs574344 single nucleotide polymorphism, an expression quantitative trait locus of GSTM1, and longevity in the Han Chinese population. MATERIALS AND METHODS: We performed a case-control study that comprised 526 long-lived subjects (>97 years of age) and 783 younger subjects (aged 19-80 years) from the general population who served as controls. Identification of the genotypes of rs574344 was accomplished by combining polymerase chain reaction with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: The long-lived study population, when compared with the controls, showed a significantly higher frequency of the T/T genotype and the T allele of rs574344. We determined that the T/T genotype is associated with a longer lifespan (OR = 5.972, 95% CI 1.798-19.833, p = 0.001, for all genders; p = 0.006 adjusted by gender). We also observed a significant difference (p < 0.05) in the distribution of alleles and genotypes in both the male group (TT vs. TA, OR = 1.043, 95% CI 1.022-1.067, p = 0.043) and the female group (TT vs. TA, OR = 3.592, 95% CI 0.982-13.147, p = 0.039) Conclusion: We found significant associations between both the T allele and the T/T genotype of rs574344 with longevity in the Han Chinese population.

Novel missense mutation in PTPN22 in a Chinese pedigree with Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis is a complex autoimmune thyroid disease, the onset of which is associated with environmental exposures and specific susceptibility genes. Its incidence in females is higher than its incidence in males. Thus far, although some susceptibility loci have been elaborated, including PTPN22, FOXP3, and CD25, the aetiology and pathogenesis of Hashimoto's thyroiditis remains unclear. METHODS: Four affected members from a Chinese family with Hashimoto's thyroiditis were selected for whole-exome sequencing. Missense, nonsense, frameshift, or splicing-site variants shared by all affected members were identified after frequency filtering against public and internal exome databases. Segregation analysis was performed by Sanger sequencing among all members with available DNA. RESULTS: We identified a missense mutation in PTPN22 (NM_015967.5; c. 77A > G; p.Asn26Ser) using whole-exome sequencing. PTPN22 is a known susceptibility gene associated with increased risks of multiple autoimmune diseases. Cosegregation analysis confirmed that all patients in this family, all of whom were female, carried the mutation. All public and private databases showed that the missense mutation was extremely rare. CONCLUSIONS: We found a missense mutation in PTPN22 in a Chinese HT pedigree using whole-exome sequencing. Our study, for the first time, linked a rare variant of PTPN22 to Hashimoto's thyroiditis, providing further evidence of the disease-causing or susceptibility role of PTPN22 in autoimmune thyroid disease. Functional studies regarding the effects of this variant on thyroid autoimmunity and thyroid function are warranted.

Mutations in EPAS1 in congenital heart disease in Tibetans.

EPAS1 encodes HIF2 and is closely related to high altitude chronic hypoxia. Mutations in the EPAS1 coding sequence are associated with several kinds of human diseases, including syndromic congenital heart disease (CHD). However, whether there are rare EPAS1 coding variants related to Tibetan non-syndromic CHD have not been fully investigated. A group of 286 Tibetan patients with non-syndromic CHD and 250 unrelated Tibetan healthy controls were recruited from Qinghai, China. Sanger sequencing was performed to identify variations in the EPAS1 coding sequence. The novelty of identified variants was confirmed by the examination of 1000G and ExAC databases. Control samples were screened to establish that the rare candidate variants were specific to the Tibetan patients with non-syndromic CHD. Bioinformatics software was used to assess the conservation of the mutations and to predict their effects. The effect of EPAS1 mutations on the transcription of its target gene, VEGF, was assessed by dual-luciferase reporter assay. The mammalian two-hybrid assay was used to study the protein interactions between HIF2 and PHD2 or pVHL. We identified two novel EPAS1 mutations (NM_001430: c.607A>C, p.N203H; c.2170G>T, p.G724W) in two patients. The N203H mutation significantly affected the transcription activity of the VEGF promoter, especially in conditions of hypoxia. The N203H mutation also showed enhanced protein-protein interactions between HIF2 and PHD2, and HIF2 and pVHL, especially in conditions of hypoxia. However, the G724W mutation did not demonstrate the same effects. Our results indicate that EPAS1 mutations might have a potential causative effect on the development of Tibetan non-syndromic CHD.

Application of a deep convolutional neural network in the diagnosis of neonatal ocular fundus hemorrhage.

There is a disparity between the increasing application of digital retinal imaging to neonatal ocular screening and slowly growing number of pediatric ophthalmologists. Assistant tools that can automatically detect ocular disorders may be needed. In present study, we develop a deep convolutional neural network (DCNN) for automated classification and grading of retinal hemorrhage. We used 48,996 digital fundus images from 3770 newborns with retinal hemorrhage of different severity (grade 1, 2 and 3) and normal controls from a large cross-sectional investigation in China. The DCNN was trained for automated grading of retinal hemorrhage (multiclass classification problem: hemorrhage-free and grades 1, 2 and 3) and then validated for its performance level. The DCNN yielded an accuracy of 97.85 to 99.96%, and the area under the receiver operating characteristic curve was 0.989-1.000 in the binary classification of neonatal retinal hemorrhage (i.e., one classification vs. the others). The overall accuracy with regard to the multiclass classification problem was 97.44%. This is the first study to show that a DCNN can detect and grade neonatal retinal hemorrhage at high performance levels. Artificial intelligence will play more positive roles in ocular healthcare of newborns and children.

Z-Scheme Au@Void@g-C3N4/SnS Yolk-Shell Heterostructures for Superior Photocatalytic CO2 Reduction under Visible Light.

Au@g-C3N4/SnS yolk-shell Z-scheme photocatalysts are fabricated by a simple template-assisted strategy. The l-cysteine can offer the amine groups and meanwhile anchor on the surface of g-C3N4 during solvothermal reaction and thus contributes greatly to the enhanced carbon dioxide adsorption capability. This Z-scheme photocatalytic reduction mechanism of Au@g-C3N4/SnS performs valuable functions in the reaction, leading to CH4 generation much earlier and higher concentration than that of Au@g-C3N4. Meanwhile, the unique yolk-shell structure can make the light bounce back and forth in the cavity and thus enhances the availability ratio of light. The application of small amount of noble metal cocatalysts and the large Brunauer-Emmett-Teller surface areas are also benefited for the enhanced photocatalytic activities. Hence, this novel material exhibits a distinguished reduction performance for CO2 reduction under visible light. The highest yields of CH4 (3.8 µmol g-1), CH3OH (5.3 µmol g-1), and CO (17.1 µmol g-1) can be obtained for the sample of Au@g-C3N4/SnS (SnS 41.5%), which is higher than other latest reported g-C3N4-based photocatalysts for CO2 photoreduction including coupled with semiconductors and noble metal cocatalysts. This strategy might represent a novel way for the effective transition of CO2 to clean fuels and can also be enormous feasible utilization in the photocatalytic field.

A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report.

BACKGROUND: Cone-rod dystrophy (CORD) is an inherited, progressive retinal disorder with genetic and phenotypic heterogeneity. Here, we aimed to identify the pathogenic mutation in affected individuals in a Chinese family with autosomal dominant cone-rod dystrophy (adCORD). METHODS: Genomic DNA and clinical examination results were collected from a Chinese family presenting with adCORD. The candidate disease-causing mutations were screened with whole-exome sequencing (WES) and bioinformatics analyses. Sanger sequencing was used for validation and cosegregation analysis. RESULTS: A novel frameshift mutation (NM_000554.4; c.538dupG:p.Val180fs) in exon 4 of the CRX gene was identified in all affected individuals in the Chinese family with adCORD. Cosegregation analysis confirmed that this mutation was cosegregated with the disease. This variant, which results in premature termination of the protein, was absent from all public variant databases or internal exome databases. CONCLUSIONS: We used whole-exome sequencing to identify a novel CRX mutation causing adCORD in a Chinese family. This study broadens the known pathogenic mutation spectrum of the CRX gene and shows the potential of WES in identifying the pathogenic mutations of CORD disease.

Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency.

BACKGROUND: To dissect the genetic alteration in two sisters with premature ovarian insufficiency (POI) from a consanguineous family. METHODS: Whole-exome sequencing technology was used in the POI proband, bioinformatics analysis was carried out to identify the potential genetic cause in this pedigree. Sanger sequencing analyses were performed to validate the segregation of the variant within the pedigree. In silico analysis was also used to predict the effect and pathogenicity of the variant. RESULTS: Whole-exome sequencing analysis identified novel and rare homozygous mutation associated with POI, namely mutation in FIGLA (c.2 T > C, start codon shift). This homozygous mutation was also harbored by the proband's sister with POI and was segregated within the consanguineous pedigree. The mutation in the start codon of the FIGLA gene alters the open reading frame, leading to a FIGLA knock-out like phenotype. CONCLUSIONS: Biallelic mutations in FIGLA may be the cause of POI. This study will aid researchers and clinicians in genetic counseling of POI and provides new insights into understanding the mode of genetic inheritance of FIGLA mutations in POI pathology.

Prevalence of refractive errors in Tibetan adolescents.

BACKGROUND: The prevalence of adolescent eye disease in remote areas of the Qinghai-Tibet Plateau has rarely been reported. To understand the prevalence of common eye diseases in Tibet, we performed ocular-disease screening on students from primary and secondary schools in Tibet, and compared the prevalence to that in the Central China Plain (referred to here as the "plains area"). METHODS: The refractive status of students was evaluated with a Spot™ vision screener. The test was conducted three or fewer times for both eyes of each student and results with best correction were recorded. RESULTS: A total of 3246 students from primary and secondary schools in the Tibet Naidong district were screened, yielding a refractive error rate of 28.51%, which was significantly lower than that of the plains group (28.51% vs. 56.92%, p < 0.001). In both groups, the prevalence of refractive errors among females was higher than that among males. CONCLUSIONS: We found that Tibetan adolescents had a lower prevalence of refractive errors than did adolescents in the plains area, which may be related to less intensive schooling and greater exposure to sunlight.

A novel mutation of HOXA11 in a patient with septate uterus.

BACKGROUND: The etiology of Müllerian duct anomalies (MDAs) is poorly understood at present. The HOXA11 gene is crucial for the development of the Müllerian duct. The objective of this study is to report a unique case of MDAs with a novel mutation in HOXA11. RESULTS: We identified a potential disease-causing mutation (p. E255K) in a patient with a septate uterus. The mutation was not detected in 169 control subjects or listed in any databases of variations. Bioinformatic predictions and functional studies showed that the mutation reduces the DNA binding affinity and disrupts transactivation ability of HOXA11. CONCLUSION: In conclusion, this is the first report to describe a HOXA11 mutation in Chinese women with MDAs. The results demonstrated that mutation in HOXA11 can contribute to the etiology of MDAs, especially the septate uterus, but might not be a common cause.

Controlled synthesis of hollow octahedral ZnCo2O4 nanocages assembled from ultrathin 2D nanosheets for enhanced lithium storage.

Hollow octahedral ZnCo2O4 nanocages assembled from ultrathin 2D nanosheets are prepared through facile fast simultaneous coordinating etching and thermal processes. Electrochemical results show that the hollow octahedral ZnCo2O4 nanocage is an outstanding anode material for LIBs with a high reversible discharge capacity of 1025 mA h g-1 at 500 mA g-1 after 200 cycles, and an outstanding rate capability of 525 mA h g-1 at 4 A g-1. Moreover, this simple, low cost and fast process could be useful for the construction of many other hollow advanced materials for supercapacitors, sensors and other novel energy and environmental applications.

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.

Retrospective investigation of retinoblastoma in Chinese patients.

This is a retrospective investigation of patients with Retinoblastoma (RB) conducted from 2013 to 2016 at the Quanzhou Maternal and Child Health Hospital (China). Demographic and clinical characteristics, treatment outcomes, and risk factors were studied. In total, 436 patients were included in the study. Most of the findings obtained in this study are consistent with other previous reports. The male: female ratio was 1.41:1, and the unilateral: bilateral ratio was 1.51:1. Leukocoria was the most common presenting sign (79.44%), followed by strabismus (12.38%). While, the overall rates of enucleation (15.82%) and mortality (0.92%) were markedly lower than in other reports of RB in Chinese, and most of the patients received conservative therapy. There were signficant differences (p < 0.001) in the age of at first sign and diagnosis, and treatment modalities between patients with bilateral and unilateral RB. The treatment modalities did not show a specific trend over the 3-year study period. Our results suggest that an incorrect initial diagnosis and long lag time may be risk factors for ineffective treatment and a poor prognosis in patients with RB. This was a comprehensive retrospective investigation in which the sample size exceeded most previous retrospective investigations of RB. Our study confirmed that early detection, accurate diagnosis, and active intervention are conducive to control of retention of patients' vision. Fundus examinations, education regarding the early signs of RB, and optimization of the therapeutic strategy of RB may play important roles in ocular health.