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1.
Oncogene ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005974

RESUMO

Thyroid cancer is the fastest growing cancer among all solid tumors in recent decades. Papillary thyroid carcinoma (PTC) is the most predominant type of thyroid cancer. Around 30% of PTC patients with distant metastases and local invasion receive poor prognosis. Thus, the identification of new druggable biological targets is of great importance. Accumulating evidence indicates that solute carrier family numbers have emerged as obligate effectors during the progression of multiple malignancies. Here, we uncovered the functional significance, molecular mechanisms, and clinical impact of solute carrier family 34 member A2 (SLC34A2) in PTC. SLC34A2 was markedly overexpressed in PTC tissues at both mRNA and protein levels compared with matched adjacent normal tissues due to promoter hypomethylation mediated by the DNA methyltransferase 3 beta (DNMT3B). Furthermore, a series of in vivo and in vitro gain- or loss-of-functional assays elucidated the role of SLC34A2 in boosting cell proliferation, cell cycle progression, migration, invasion, and adhesion of PTC cells. Using immunoprecipitation and mass spectrometry, we discovered that SLC34A2 bound to the actin-binding repeats domain of Cortactin (CTTN), thereby inducing the invadopodia formation of PTC cells to promote the metastasis potential of PTC cells. Besides, our mechanistic studies, as well as gene set enrichment analysis (GSEA), have pinpointed the PTEN/AKT/FOXO3a pathway as a major signaling functioning downstream of SLC34A2 regulated cell growth. Taken together, our results highlighted that SLC34A2 plays a pivotal oncogenic role during carcinogenesis and metastasis through distinct mechanisms in PTC.

2.
Bone Joint Res ; 8(8): 405-413, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31537998

RESUMO

Objectives: X-linked hypophosphataemic rickets (XLHR) is a disease of impaired bone mineralization characterized by hypophosphataemia caused by renal phosphate wasting. The main clinical manifestations of the disorder are O-shaped legs, X-shaped legs, delayed growth, and bone pain. XLHR is the most common inheritable form of rickets, with an incidence of 1/20 000 in humans. It accounts for approximately 80% of familial cases of hypophosphataemia and serves as the prototype of defective tubular phosphate (PO43+) transport, due to extra renal defects resulting in unregulated FGF23 activity. XLHR is caused by loss-of-function mutations in the PHEX gene. The aim of this research was to identify the genetic defect responsible for familial hypophosphataemic rickets in a four-generation Chinese Han pedigree and to analyze the function of this mutation. Methods: The genome DNA samples of all members in the pedigree were extracted from whole blood. We sequenced all exons of the PHEX and FGF23 genes, as well as the adjacent splice site sequence with Sanger sequencing. Next, we analyzed the de novo mutation c.1692 del A of the PHEX gene with an online digital service and investigated the mutant PHEX with SWISS-MODEL, immunofluorescence, and protein stability detection. Results: Through Sanger sequencing, we found a de novo mutation, c.1692 del A, in exon 16 of the PHEX gene in this pedigree. This mutation can make the PHEX protein become unstable and decay rapidly, which results in familial XLHR. Conclusion: We have found a de novo loss-of-function mutation, c.1692 del A, in exon 16 of the PHEX gene that can cause XLHR.Cite this article: J. Huang, X. Bao, W. Xia, L. Zhu, J. Zhang, J. Ma, N. Jiang, J. Yang, Q. Chen, T. Jing, J. Liu, D. Ma, G. Xu. Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets. Bone Joint Res 2019;8:405-413. DOI: 10.1302/2046-3758.88.BJR-2018-0276.R1.

3.
Oncol Rep ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31524279

RESUMO

Previous research from our group revealed that the long coding RNA (lncRNA) linc01105 is associated with neuroblastoma proliferation and apoptosis, and that its expression is correlated with the International Neuroblastoma Staging System stage. The purpose of the present study was to investigate the functions of Linc01105 in neuroblastoma. Lentivirus­mediated linc01105 knockdown was performed in the neuroblastoma cell line SH­SY5Y. The expression levels of linc01105 and of other associated genes were measured by reverse transcription­quantitative PCR. Cell Counting Kit­8 assay and flow cytometry were used to determine cell viability and apoptosis. The levels of proteins were detected using western blot analysis. Bioinformatics analysis and luciferase reporter assays were used to examine the relationship between linc01105, miR­6769b­5p and vascular endothelial growth factor A (VEGFA). Angiogenesis ability was measured using a tube formation assay. The results demonstrated that HIF­1α overexpression promoted the transcription of linc01105 by acting as a transcription factor. Knockdown of linc01105 inhibited neuroblastoma cell proliferation, migration and invasion, and it induced apoptosis. In addition, linc01105 affected the expression of p53 and Bcl­2 family proteins and activated the caspase signaling pathway. Further functional experiments revealed that linc01105 promoted the expression of the miR­6769b­5p target gene VEGFA by acting as a sponge of miR­6769b­5p. In conclusion, linc01105 may contribute to neuroblastoma tumorigenesis and development. The present findings indicated that the interplay between the p53/caspase pathway and the linc01105/miR­6769b­5p/VEGFA axis may have important roles in the development of neuroblastoma.

4.
J Cell Mol Med ; 23(10): 6978-6988, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31410985

RESUMO

Recent studies have demonstrated that aberrant long non-coding RNAs (lncRNAs) expression are suggested to be closely associated with multiple human diseases, lung cancer included. However, the roles of lncRNAs in lung cancer are not well understood. In this study, we used microarrays to investigate the aberrantly expressed lncRNAs in the mouse lung adenocarcinoma with P53 knockout and the KrasG12D mutation. Results revealed that 6424 lncRNAs were differentially expressed (≥ 2-fold change, P < .05). Two hundred and ten lncRNAs showed more than 8-fold change and conserved across human and were further analysed in the primary mouse lung adenocarcinoma KP cells, which were isolated from the p53 knockout and the KrasG12D mutation mice. Among all the 210 lncRNAs, 11 lncRNAs' expression was regulated by P53, 33 lncRNAs by KRAS and 13 lncRNAs by hypoxia in the primary KP cells, respectively. NONMMUT015812, which was remarkably up-regulated in the mouse lung adenocarcinoma and negatively regulated by the P53 re-expression, was detected to analyse its cellular function. Results showed that knockdown of NONMMUT015812 by shRNAs decreased proliferation and migration abilities of KP cells. Among those aberrantly expressed lncRNAs in the mouse lung adenocarcinoma, NONMMUT015812 was a potential oncogene.

5.
Neurogastroenterol Motil ; 31(11): e13696, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31389109

RESUMO

BACKGROUND: It is unknown whether cognitive dysfunction found in patients with irritable bowel syndrome (IBS) was attributable to the different subtypes, ongoing pathophysiological processes, trait characteristics, or psychiatric comorbidity. METHODS: Forty Rome-III patients with IBS (20 diarrhea-predominant [IBS-D] and 20 constipation-predominant [IBS-C]) and 40 age-, sex-, education-matched healthy controls were systematically recruited and compared on their cognitive function with continuous performance test (CPT), Wisconsin Card Sorting Test (WCST) and emotional Stroop test. Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Patient Health Questionnaire-15 (PHQ-15) and a structured bowel symptom questionnaire were performed to measure anxiety, depressive, somatization, and bowel symptoms, respectively. Psychiatric diagnoses were ascertained with SCID-I (Structured Clinical Interview for DSM-IV Axis I Disorders). KEY RESULTS: Patients with IBS showed significantly increased standard deviation of reaction time (SDRT) (P = .003) on CPT, increased failure to maintain set (FMS) (P=.002), and percentage of perseverative errors (P = .003) on WCST. SDRT did not correlate with illness chronicity or bowel symptoms. FMS correlated with bowel symptom severity. In logistic regression models controlled for BAI, BDI-II, and PHQ-15, SDRT (AOR = 1.08, P = .025), but not FMS (P = .25) or percentage of perseverative errors (P = .24), significantly differentiated IBS from controls. Cognitive function was not significantly different between IBS-C and IBS-D (P > .05), or between pure IBS (n = 22) and IBS with generalized anxiety disorder (GAD) (n = 17) (P > .05). CONCLUSIONS & INFERENCES: Patients with IBS showed attentional and executive function impairment irrespective of subtypes but otherwise heterogeneous in terms of its state-trait correlations and overlap with anxiety comorbidity.

6.
Clin Genet ; 96(5): 402-410, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328266

RESUMO

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

7.
Clin Genet ; 96(4): 300-308, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231791

RESUMO

Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. More than 40 genes have been identified as causative genes for autosomal dominant non-syndromic hearing loss (ADNSHL), but there are many other candidate genes that remain to be discovered. We aimed to identify the causative gene mutation for post-lingual progressive ADNSHL in a Chinese family. Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant (NM_ 001244580, c.511C>T, p.Arg171Cys) in the TRansformation/tRanscription domain-Associated Protein gene associated with hearing loss in a three-generation Chinese family with ADNSHL). Additionally, three more novel variants of transformation/transcription domain associated protein (TRRAP) were detected in 66 sporadic cases of hearing loss. Morpholino oligonucleotides knockdown and clustered regularly interspaced short palindromic repeats/Cas9 knockout zebrafish were constructed to validate the genetic findings. Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development. In conclusion, TRRAP (NM_ 001244580, c.511C>T, p.Arg171Cys) co-segregated with hearing loss in a Chinese family with ADNSHL, and TRRAP deficiency caused hearing disability in zebrafish, suggesting TRRAP is a gene associated with ADNSHL.

8.
FEBS Lett ; 593(15): 2008-2018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31198993

RESUMO

Hereditary hearing impairment is a clinically and genetically heterogeneous disease. Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. The pathogenic variant of the gene encoding human topoisomerase IIß TOP2B (c.G4837C:p.D1613H) was cosegregated with hearing loss in this pedigree and another two variants of TOP2B were detected in 66 sporadic patients with hearing loss. top2b knockdown led to significant defects in zebrafish inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling. As a result, supporting cell and hair cell numbers were reduced through inhibition of the PI3K-Akt pathway. Therefore, we hypothesized that mutations in TOP2B can cause autosomal-dominant nonsyndromic hearing impairment through inhibition of the PI3K-Akt signalling pathway. DATABASE: The whole-exome sequence data in the study are available at the Sequence Read Archive database (NCBI) under the accession numbers SRR9050868, SRR9050867, SRR90508676, SRR90508675, SRR90508674, SRR90508673, SRR90508672, SRR90508671, SRR90508679, SRR90508670, SRR9050859. SRR9050858 and SRR9050857, respectively.

9.
BMC Med Genomics ; 12(1): 75, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138201

RESUMO

BACKGROUND: TBX20 plays an important role in heart development; however, its epigenetic regulation in the pathogenesis of tetralogy of Fallot (TOF) remains unclear. METHODS: The methylation levels of the TBX20 promoter region in the right ventricular myocardial tissues of TOF and control samples were measured by the Sequenom MassARRAY platform. Bisulphite-sequencing PCR (BSP) was used to confirm the TBX20 methylation of CpG sites in cells. Dual-luciferase reporter assays were performed to detect the influence of TBX20 methylation and Sp1 transcription factors on gene activity. An electrophoretic mobility shift assay (EMSA) was used to explore the binding of the Sp1 transcription factor to the TBX20 promoter. RESULTS: TOF cases had a significantly lower TBX20_M1 methylation level than controls (median methylation: 20.40% vs. 38.73%; p = 0.0047). The Sp1 transcription factor, which binds to Sp1 binding sites in the TBX20_M1 region and promotes TBX20 gene activity, was blocked by the methylation of Sp1 binding sites in normal controls. With decreasing methylation in the TOF cases, the Sp1 transcription factor can bind to its binding site within the TBX20 promoter M1 region and promote TBX20 gene expression. CONCLUSIONS: Hypomethylation of the TBX20 promoter region was observed in the TOF cases, and the high expression of the TBX20 gene may be caused by activated Sp1 transcription factor binding because of the decreasing methylation at the Sp1 transcription factor binding sites within TBX20_M1.


Assuntos
Metilação de DNA , Proteínas com Domínio T/genética , Tetralogia de Fallot/genética , Sequência de Bases , Sítios de Ligação , Estudos de Casos e Controles , Epigênese Genética , Feminino , Células HEK293 , Humanos , Lactente , Masculino , Fator de Transcrição Sp1/metabolismo , Transcrição Genética/genética
10.
Sci Rep ; 9(1): 6683, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040315

RESUMO

Congenital heart diseases (CHDs) are the most common types of birth defects, affecting approximately 1% of live births and remaining the leading cause of mortality. CHD patients often show a higher incidence of heterotaxy syndrome. However, the exact aetiology of CHD and heterotaxy syndrome remains unclear. In this study, targeted sequencing and Sanger sequencing were performed to analyze the exonic regions of 37 primary ciliary dysfunction (PCD)- related candidate genes in 42 CHD patients with heterotaxy syndrome. Variants affecting protein-coding regions were filtered according to databases of known variants and predicted in silico using functional prediction program. Thirty-four potential disease-causing heterozygous variants in 11 genes were identified in the 19 CHD patients with heterotaxy syndrome (45.2%, 19/42). The DNAH11 gene showed the highest mutation rate (16.7%; 14 of 84 alleles) among the CHD patients with heterotaxy. Fisher's exact test revealed a significant association of DNAH11 variants with CHD and heterotaxy (P = 0.0001). In families, six different compound heterozygous variants of DNAH11 were validated in family 1-5031 (p.W802X/p.M282I), family 2-5045 (p.T3460K/p.G4425S), family 3-5065 (p.G447R/p.L1157R), family 4-5130 (p.I2262T/p.D3800H), family 5-5707 (p.S1823fs/p.F2759L/p.R4395X) and family 6-5062 (p.D3610V/p.I243V). These findings suggest that the DNAH11 variants are significantly associated with CHD and heterotaxy syndrome and that compound heterozygous DNAH11 variants may be the common genetic cause of the development of familial CHD and heterotaxy syndrome.

11.
Int Psychogeriatr ; 31(8): 1099-1107, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31030690

RESUMO

OBJECTIVE: The study of predeath grief is hampered by measures that are often lengthy and not clearly differentiated from other caregiving outcomes, most notably burden. We aimed to validate a new 11-item Caregiver Grief Questionnaire (CGQ) assessing two dimensions of predeath grief, namely relational deprivation and emotional pain. DESIGN: Cross-sectional survey. SETTING: Community and psychogeriatric clinics. PARTICIPANTS: 173 Alzheimer (AD) caregivers who cared for relatives with different degrees of severity (63 mild, 60 moderate, and 50 severe). MEASUREMENTS: Besides the CGQ, measures of caregiver burden and depressive symptoms, and care-recipients' neuropsychiatric symptoms and functional impairment were assessed. RESULTS: Confirmatory factor analysis supported the hypothesized 2-factor over the 1-factor model, and both subscales were only moderately correlated with burden. Two-week test-retest reliabilities were excellent. Caregivers for mild AD reported less grief than those caring for more severe relatives. Z tests revealed significantly different correlational patterns for the two dimensions, with emotional pain more related to global burden and depressive symptoms, and relational deprivation more related to care-recipients' functional impairment. Both dimensions were mildly correlated with neuropsychiatric symptoms (especially disruptive behaviors and psychotic symptoms) of the care-recipient. CONCLUSIONS: Results supported the reliability and validity of the two-dimensional measure of predeath grief. As a brief measure, it can be readily added to research instruments to facilitate study of this important phenomenon along with other caregiving outcomes.

12.
J Cell Mol Med ; 23(6): 4454-4463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016877

RESUMO

Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia disorder. ANK1 mutations account for most HS cases, but pathogenicity analysis and functional research have not been widely performed for these mutations. In this study, in order to confirm diagnosis, gene mutation was screened in two unrelated Chinese families with HS by a next-generation sequencing (NGS) panel and then confirmed by Sanger sequencing. Two novel heterozygous mutations (c.C841T, p.R281X and c.T290G, p.L97R) of the ANK1 gene were identified in the two families respectively. Then, the pathogenicity of the two new mutations and two previously reported ANK1 mutations (c.C648G, p.Y216X and c.G424T, p.E142X) were studied by in vitro experiments. The four mutations increased the osmotic fragility of cells, reduced the stabilities of ANK1 proteins and prevented the protein from localizing to the plasma membrane and interacting with SPTB and SLC4A1. We classified these four mutations into disease-causing mutations for HS. Thus, conducting the same mutation test and providing genetic counselling for the two families were meaningful and significant. Moreover, the identification of two novel mutations enriches the ANK1 mutation database, especially in China.

13.
Hum Gene Ther ; 30(2): 155-167, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30122074

RESUMO

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene. Enzyme replacement treatment is the most effective therapy available for type 1 GD patients, but it is very expensive and does not improve neurologic outcomes in type 2 and 3 GD patients. This study evaluated the effectiveness of an adeno-associated virus 9 (AAV9) vector expressing the Gba gene delivered systemically in GD mouse models. To detect the therapeutic effects of the AAV9-mediated Gba transfer on the systemic symptoms of GD, an inducible whole-body Gba knockout mouse was developed in which tamoxifen effectively induced whole-body Gba gene deletion, and the mice displayed systemic symptoms of GD. The AAV9-CMV-Gba vector, with the expression of Gba driven by the universal CMV promoter, restored GCase activity in multiple organs and prolonged the lifespan in tamoxifen-induced GD mice after intravenous injection. Mice with brain-specific Gba deletion were also included in this study as a model of neuropathic GD (nGD) and injected intraperitoneally on postnatal day 5 with the AAV9-SYN-Gba vector; this improved the GCase activity, ameliorated the neuropathological changes and extended the mean lifespan two-fold. This study demonstrates that AAV9-mediated gene transfer is a potentially effective treatment for GD.

14.
J Breast Cancer ; 21(3): 330-333, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30275862

RESUMO

In this study, we used next-generation sequencing methods to screen 300 individuals for BRCA1 and BRCA2. A novel mutation (c.849dupT) in BRCA2 was identified in a female patient and her unaffected brothers. This mutation leads to the truncation of BRCA2 functional domains. Moreover, BRCA2 mRNA expression levels in mutation carriers are significantly reduced compared to noncarriers. Immunofluorescence and western blot assays showed that this mutation resulted in reduced BRCA2 protein expression. Thus, we identified a novel mutation that damaged the function and expression of BRCA2 in a family with breast cancer history. The pedigree analysis suggested that this mutation is strongly associated with familial breast cancer. Genetic counsellors suggest that mutation carriers in this family undergo routine screening for breast cancer, as well as other malignancies, such as prostate and ovarian cancer. The effects of this BRCA2 mutation on drug resistance should be taken into consideration during treatment.

15.
PLoS Genet ; 14(8): e1007578, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30110327

RESUMO

SMYD4 belongs to a family of lysine methyltransferases. We analyzed the role of smyd4 in zebrafish development by generating a smyd4 mutant zebrafish line (smyd4L544Efs*1) using the CRISPR/Cas9 technology. The maternal and zygotic smyd4L544Efs*1 mutants demonstrated severe cardiac malformations, including defects in left-right patterning and looping and hypoplastic ventricles, suggesting that smyd4 was critical for heart development. Importantly, we identified two rare SMYD4 genetic variants in a 208-patient cohort with congenital heart defects. Both biochemical and functional analyses indicated that SMYD4(G345D) was pathogenic. Our data suggested that smyd4 functions as a histone methyltransferase and, by interacting with HDAC1, also serves as a potential modulator for histone acetylation. Transcriptome and bioinformatics analyses of smyd4L544Efs*1 and wild-type developing hearts suggested that smyd4 is a key epigenetic regulator involved in regulating endoplasmic reticulum-mediated protein processing and several important metabolic pathways in developing zebrafish hearts.


Assuntos
Epigênese Genética , Histona Metiltransferases/fisiologia , Histona-Lisina N-Metiltransferase/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Peixe-Zebra/genética , Adolescente , Animais , Sistemas CRISPR-Cas , Criança , Pré-Escolar , Estudos de Coortes , Modelos Animais de Doenças , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Coração/efeitos dos fármacos , Coração/embriologia , Cardiopatias Congênitas/genética , Histona Desacetilase 1/genética , Histona Desacetilase 1/fisiologia , Histona Metiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Conformação Proteica , Análise de Sequência de RNA , Transcriptoma , Sequenciamento Completo do Exoma , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética
16.
Sci Rep ; 8(1): 12386, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120289

RESUMO

Heterotaxy syndrome (HTX) is characterized by left-right (LR) asymmetry disturbances associated with severe heart malformations. However, the exact genetic cause of HTX pathogenesis remains unclear. The aim of this study was to investigate the pathogenic mechanism underlying heterotaxy syndrome. Targeted next-generation sequencing (NGS) was performed for twenty-two candidate genes correlated with LR axis development in sixty-six HTX patients from unrelated families. Variants were filtered from databases and predicted in silico using prediction programs. A total of twenty-one potential disease-causing variants were identified in seven genes. Next, we used Sanger sequencing to confirm the identified variants in the family pedigree and found a novel hemizygous mutation (c.890G > T, p.C297F) in the ZIC3 gene in a male patient that was inherited from his mother, who was a carrier. The results of functional indicated that this ZIC3 mutation decreases transcriptional activity, affects the affinity of the GLI-binding site and results in aberrant cellular localization in transfected cells. Moreover, morpholino-knockdown experiments in zebrafish demonstrated that zic3 mutant mRNA failed to rescue the abnormal phenotype, suggesting a role for the novel ZIC3 mutation in heterotaxy syndrome.


Assuntos
Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/diagnóstico , Síndrome de Heterotaxia/genética , Proteínas de Homeodomínio/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Animais , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Radiografia Torácica , Tomografia Computadorizada por Raios X , Fatores de Transcrição/metabolismo , Ativação Transcricional , Adulto Jovem , Peixe-Zebra
17.
Cell Death Dis ; 9(8): 782, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013073

RESUMO

The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.

18.
Sheng Wu Gong Cheng Xue Bao ; 34(6): 956-963, 2018 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-29943541

RESUMO

PPP2R2A is one of the regulatory subunits of the PP2A phosphatase complexes, and previous studies showed that its upregulation promotes cancer cell survival and growth. In this research, we used the tandem affinity purification and the HPLC-Chip-ESI/MS/MS mass spectrometry to screen the PPP2R2A-binding proteins and the results indicated that the GFPT-1/-2 were the potential partners of PPP2R2A. We further validated the interaction between PPP2R2A and GFPT-1/-2 through GST Pull-down, co-immunoprecipitation and immunofluorescence assays. And we found that knockdown of PPP2R2A by lentivirus-mediated shRNA enhanced the phosphorylation of GFPT2, whereas the phosphorylation of GFPT1 had no significant change. GFPT2 is a rate-limiting enzyme in the hexosamine pathway. Our results showed that the knockdown of PPP2R2A promoted the total cellular O-GlcNAcylation in MDA-MB-231 breast cancer cells. These results suggest that PPP2R2A interacts with GFPT1/2, and leads to the phosphorylation of GFPT2, which can regulate the cellular O-GlcNAcylation.


Assuntos
Neoplasias da Mama/metabolismo , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/metabolismo , Proteína Fosfatase 2/metabolismo , Acilação , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Humanos , Fosforilação , Espectrometria de Massas em Tandem , Regulação para Cima
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(1): 1-8, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29419850

RESUMO

The widespread application of next generation sequencing (NGS) in clinical settings has enabled testing, diagnosis, treatment and prevention of genetic diseases. However, many issues have arisen in the meanwhile. One of the most pressing issues is the lack of standards for reporting genetic test results across different service providers. The First Forum on Standards and Specifications for Clinical Genetic Testing was held to address the issue in Shenzhen, China, on October 28, 2017. Participants, including geneticists, clinicians, and representatives of genetic testing service providers, discussed problems of clinical genetic testing services across in China and shared opinions on principles, challenges, and standards for reporting clinical genetic test results. Here we summarize expert opinions presented at the seminar and report the consensus, which will serve as a basis for the development of standards and guidelines for reporting of clinical genetic testing results, in order to promote the standardization and regulation of genetic testing services in China.


Assuntos
Consenso , Testes Genéticos/métodos , Testes Genéticos/normas , Guias de Prática Clínica como Assunto , China , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
20.
J Cell Physiol ; 233(9): 6841-6852, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29336484

RESUMO

Plant homeodomain finger 2 (PHF2) is a JmjC family histone demethylase that demethylates H3K9me2, a repressive gene marker. PHF2 was found to play a role in the differentiation of several tissue types such as osteoblast and adipocyte differentiation. We report here that PHF2 plays a role in the epigenetic regulation of megakaryocytic (MK) and erythroid differentiation. We investigated PHF2 expression during MK and erythroid differentiation in K562 and human CD34+ progenitor (hCD34+ ) cells. Our data demonstrate that PHF2 expression is down-regulated during megakaryopoiesis and erythropoiesis. PHF2 has a negative role in MK and erythroid differentiation of K562 cells; knockdown of PHF2 promotes MK and erythroid differentiation of hCD34+ cells. Similarly, we found that p53 expression is also down-regulated during MK and erythroid differentiation, which parallels PHF2 expression. PHF2 binds to the p53 promoter and regulates the expression of p53 by demethylating H3K9me2 in the promoter region of p53. Taken together, our data show that PHF2 is a negative epigenetic regulator of MK and erythroid differentiation, and that one of the pathways through which PHF2 affects MK and erythroid differentiation is via regulation of p53 expression.


Assuntos
Diferenciação Celular/genética , Epigênese Genética/genética , Células Eritroides/patologia , Histona Desmetilases/genética , Histonas/genética , Proteínas de Homeodomínio/genética , Megacariócitos/fisiologia , Antígenos CD34/genética , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/genética , Eritropoese/genética , Células HEK293 , Humanos , Células K562 , Osteoblastos/fisiologia , Regiões Promotoras Genéticas/genética , Proteína Supressora de Tumor p53/genética
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