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Objective:To predict the transmembrane structure of transmembrane protein 26 (TMEM26), observe its expression in human retina and mouse retina, and investigate the relationship between it and primary open-angle glaucoma (POAG).Methods:The transmembrane structure of TMEM26 in human and mouse was obtained by inputting its amino acid sequences into the transmembrane protein structure prediction software, MemBrain.The expression and location of TMEM26 in human and mouse retinas were observed through frozen retinal sections stained with anti-TMEM26 antibody, which came from a human donor and five SPF-grade C57BL/6 mice.The possible function of TMEM26 gene and its influence on eyes were inferred on the basis of the specific expression of TMEM26 in retina.The single nucleotide polymorphism mutation of TMEM26 gene was searched in literature related to ocular diseases.The use and care of animals complied with the Regulations on the Management of Experimental Animals.This research protocol was approved by an Ethics Committee of Sichuan Provincial People's Hospital (No.2019-36). Results:Both human and mouse TMEM26 were eight transmembrane proteins with similar eight hydrophobic transmembrane domains, four hydrophilic cytoplasmic domains and five hydrophilic extracellular membrane domains.Small differences in the number of amino acid residues in the domains of TMEM26 were found.In both human and mouse retina, TMEM26 gene was only specifically expressed in the outer plexiform layer (OPL)and inner plexiform layer (IPL). TMEM26 was weakly associated with POAG in a published data. Conclusions:TMEM26 is a multi-pass transmembrane protein, mainly expressed in IPL and OPL of the retina. TMEM26 gene is weakly related to POAG.
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Objective:To investigate the association between choroidal neovascularization (CNV) and the LIPC gene single nucleotide polymorphism (SNP) in a Chinese Han population from Shantou. Methods:A case-control study was designed.Two hundred and twenty-one patients with CNV who visited Shantou International Eye Center from January 2010 to December 2016 were enrolled and served as the CNV group, and 430 healthy volunteers matched in age and gender were enrolled and served as the normal control group.Each of 5 ml fasting peripheral blood of the subjects was extracted, and peripheral blood DNA was extracted after anticoagulation.PCR amplification was conducted on SNP loci of LIPC gene including rs10468017, rs920915 and rs2070895.After purification, genotyping was performed on the above SNP loci using the single base extension (SNaPshot) method.Hardy-weinberg equilibrium (HWE) test was used to determine the genotype frequency of the three SNPs of LIPC gene.The gene frequency and genotype frequency of the 3 loci between the CNV group and normal control group were compared.This study followed the Declaration of Helsinki.Written informed consent was obtained from each subject prior to entering the study cohort.The study protocol was approved by the Ethics Committee of Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong (No.11-004). Results:The genotype frequency distribution of rs10468017, rs920915 and rs2070895 of the three SNPs of LIPC gene reached genetic balance in the total samples ( P>0.05). The genotype frequencies of rs10468017 TT genotype, rs920915 CC genotype and rs2070895 AA genotype in CNV group were 3.62%, 5.43% and 12.22%, respectively, while those of normal control group were 2.56%, 5.58% and 14.19%, respectively, with no statistically significant difference (all at P>0.05). The minimum allele (T) frequency of rs10468017 was 18.1% and 17.2%, the minimum allele (C) frequency of rs920915 was 21.7% and 23.1%, and the minimum allele (A) frequency of rs2070895 was 33.7% and 38.7% in the CNV group and the normal control group, respectively (all at P>0.05). The odd ratio ( OR) values (95%confidence interval [ CI]) of rs10468017, rs920915 and rs2070895 in the CNV group and the normal control group were 1.06 (0.79-1.44), 0.92 (0.70-1.21) and 0.80 (0.63-1.02), respectively. Conclusions:The results from the present study do not indicate the association of LIPC SNPs (rsl0468017, rs920915 and rs2070895) with CNV in the Shantou Han population.
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Objective:To investigate the association between rs284489 in the 8q22 region and primary open angle glaucoma (POAG) in Sichuan, and the association between rs284489 and gender difference.Methods:A case control study was adopted.A total of 894 Han Nationality POAG patients in Sichuan People's Hospital from September 2015 to March 2017 were included, and 994 control patients who participated in physical examination in the same period were included.All subjects had no blood relationship and all were Han Chinese.Each sample of 4 ml-peripheral blood was collected for extracting DNA and rs284489 information was obtained from NCBI website.Primers 5.0 software was used to design primers.Genotyping was performed by using a tailored "Chinese-Chip" for association analysis of the rs284489 in the 8q22 region.Genotype allele frequencies and Hardy-Weinberg equilibrium (HWE) were assessed by using χ2 test.Logistic regression was applied to adjust for gender differences between the cases and controls.The PS; Power and Sample Size Calculation (version 3.1.2) software was used to calculate statistical power.This study followed the Declaration of Helsinki.This study followed the guidelines for the collection of human genetic disease specimens issued by the Ministry of Health of China.The study protocol was approved by the Ethics Committee of Sichuan Provincial People's Hospital (No.2016-58). Results:The allele distribution of rs284489 was within the HWE for both case and control groups (both at P>0.05). The difference of the minor allele-G distribution between the case group and the control group was not significant (allelic P*=0.94, OR [95% CI] **=1.01[0.83-1.23]); To further investigate the association between rs284489 and POAG, four genetic models, including model 1 (AG vs. AA), additive model 2 (GG vs.AA), dominant model (GG+ AG vs.AA), and recessive model (GG vs.AG+ AA) were applied.There was no significant difference in the four genetic models between the case and control groups (adjusted P# additive model 1 =0.26, P# additive model 2 =0.54, P# dominant model =0.50, P# recessive model =0.25); the gender difference in this study was not associated with the polymorphism of rs284489 (adjusted P#=1.00, crude OR [95% CI]=1.00[0.88-1.14], adjusted OR [95% CI]=1.00 [0.87-1.14]). Conclusions:rs284489 is not statistically associated with POAG in a Sichuan Han Chinese population.
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Objective:To detect whether Toll-like receptor 4 ( TLR4) polymorphisms contributed to primary open angle glaucoma (POAG) in a Chinese population. Methods:A Chinese cohort, including 799 unrelated POAG patients and 799 unrelated controls, was enrolled in our case-control association study. The data was collected at Sichuan Provincial People's Hospital from May 2014 to March 2018. TLR4 functional single nucleotide polymorphisms (SNPs), including rs4986790 and rs4986791, were genotyped by SNaPshot method. Genotype and allele frequencies of the two SNPs were evaluated. This study was approved by the Institutional Review Boards of the Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (No.2016-58), and complied with the guidelines of the Declaration of Helsinki. Written informed consents were obtained from all subjects prior to the study. Results:Allelic association analysis revealed that there were no significant association detected in the allelic distributions between the POAG cases and controls for SNPs rs4986790 ( P=0.317) and rs4986791 ( OR=1.000, 95% CI =0.062 5-16.002 2, P=1.000) in the TLR4 gene. Conditional analysis of the two SNPs did not show any significant difference in genotype and allele frequency between the case and the control groups. No association of the two SNPs with POAG was detected under four different genetic models, including homozygote, heterozygote, dominant and recessive models. Conclusions:Polymorphisms rs4986790 and rs4986791 in the TLR4 gene are not related to POAG in the Chinese cohort.
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Wet age-related macular degeneration (wAMD) is caused by choroidal neovascularization (CNV), which occurs when the choroidal new capillaries reach the RPE layer and photoreceptor cell layer through the ruptured Bruch membrane, leading to neovascularization bleeding, leakage, and scarring. In view of the important role of VEGF in the development of CNV, targeted therapy with various intraocular anti-VEGF drugs is the first-line treatment for wAMD. However, the efficacy of anti-VEGF drugs in the treatment of wAMD is affected by a variety of factors, and some patients still have problems such as unresponsiveness, drug resistence, tachyphylaxis, long-term repeated injections, and severe adverse effects. It is the direction of future researches to deeply explore the physiological and pathological process of wAMD, find the cause of CNV formation, and seek better therapies.
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OBJECTIVE@#To screen for MYOC gene variants among sporadic patients with primary open angle glaucoma (POAG).@*METHODS@#For 398 patients with POAG, Sanger sequencing was applied to detect potential variants of the MYOC gene.@*RESULTS@#Eight patients (2.0%) were found to harbor variations of the MYOC gene. These included five types of variants, among which c.667C>T (p.Pro223Ser) and c.1138G>T (p.Asp380Tyr) were novel. c.382C>T (p.Arg128Trp), c.1109C>T(p.Pro370Leu) and c.1130C>A (p.Thr377Lys) were previously associated with POAG. Alignment of amino acid sequences of MYOC proteins of various species revealed that the two novel variants have occurred at highly conserved positions. c.1138G>T was predicted to be possible pathogenic by Bioinformatic analysis.@*CONCLUSION@#Two novel variants of the MYOC gene were detected among sporadic POAG patients, which enriched its variant spectrum.
Subject(s)
Humans , Cytoskeletal Proteins , Genetics , Eye Proteins , Genetics , Glaucoma, Open-Angle , Genetics , Glycoproteins , Genetics , MutationABSTRACT
Objective To explore the rare nonsynonymous variants of ABCA1 gene in primary open angle glaucoma (POAG).Methods A prospective cohort study was carried out.Three hundred and ninety-eight POAG patients and 198 healthy controls matched in age and gender were recruited from March 2017 to March 2018 in Eye and Ear Nose Throat (ENT) Hospital of Fudan University.The periphery blood of 2-5 ml from all the subjects was collected for extraction of DNA,and rare variant analysis of the ABCA1 gene was conducted by whole exome sequencing (WES) data of these subjects.The study protocol was approved by Ethic Committee of Eye and Ear Nose Throat Hospital of Fudan University and Sichuan Provincial People's Hospital (No.2016-32-1,and written informed consent was obtained from each subject prior to entering the study cohort.Results A total of 21 rare nonsynonymous variants (minor allele frequency MAF＜0.O1) were detected in the coding regions of ABCA1 gene in 27 subjects of the 398 POAG,with the detection rate of 6.8％.Among them,c.4310C＞A (p.Thr1437Asn),c.3772G＞T(p.Asp1258Tyr),c.775A＞G (p.Lys259Glu) and c.1507_1508insGAGGT (p.Glu503GlyfsX7) were four novel variants.In the 198 healthy controls,five rare nonsynonymous variants were detected in the ABCA1 gene from five subjects respectively,with the detection rate of 2.5％,the detection rate of nonsynonymous in POAG group was higher than that in healthy control group,showing a significant difference (x2=4.72,P =0.03,OR =2.81).Conclusions Rare nonsynonymous variants in ABCA1 is associated with the pathogenesis of POAG.These variants can enrich the variation spectrum of ABCA1.
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<p><b>OBJECTIVE</b>To detect potential mutations of fibrillin-1 (FBN1) gene in a child with Marfan syndrome (MFS) and explore its molecular pathogenesis.</p><p><b>METHODS</b>The 66 exons of the FBN1 gene were analyzed by direct sequencing. SIFT and PolyPhen-2 were used to predict the structural and functional changes at the protein level.</p><p><b>RESULTS</b>A novel heterozygous mutation c.3998 G>A (p.Cys1333Tyr) was found in exon 32 in the child. The same mutation was not found among his unaffected family members and 683 healthy controls. Multiple sequence alignment showed that this novel mutation was located in a highly conserved region of the FBN1 protein across various species and may induce structural change to a functional domain.</p><p><b>CONCLUSION</b>The novel c.3998G>A (p.Cys1333Tyr) mutation of the FBN1 gene probably predisposed the MFS in the child. Above finding has enriched the spectrum of FBN1 mutations.</p>
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Objective To screen the pathogenic locus and gene in a primary open angle glaucoma(POAG),and to provide a basis for molecular genetic study of POAG.Methods A POAG pedigree with 35 members was diagnosed in Sichuan peoples' Hospital from January to August 2005.The disease history and clinical data were collected.Genome-wide scan was performed for the families.Specific software was used to calculate the LOD value,which based on the allele (haploid) typing result with two-point method to definite the positive loci by the largest LOD value.Results The POAG family had 35 members of 4 generations.18 patients were diagnosed as juvenile open angle glaucoma from visual disc shape abnormality and loss of typical visual field.All of the patients in this family suffered various degrees of binocular vision loss and vision loss in childhood,with poorly visual function.The LOD values of 3 short tandom repeat (STR) markers on chromosome 2 were greater than 3.0,they were D2S2369 (LOD value 4.0033),D2S2332 (LOD value 3.8402) and D2S337 (LOD value 4.7520).There was a genetic linkage near the three genetic markers in the family.The primary glaucoma positive locus was a in chromosome p15 to chromosome p16.2,and the genetic distance was about 9 Mb,locating in between the markers D2S2369 and D2S2397.Conclusions GLCIH is a pathogenic locus for this POAG pedigree,which supplies an evidence for elucidating the pathogenesis of POAG.
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<p><b>OBJECTIVE</b>To assess the association of single nucleotide polymorphisms (SNPs) of PLEKHA7, COL11A1 and PCMTD1-ST18 genes and primary angle closure glaucoma (PACG) among ethnic Han Chinese from Sichuan Province.</p><p><b>METHODS</b>In this study, 362 subjects with PACG and 1056 age- and sex-matched healthy controls were recruited. Genotypes of 3 reported SNPs, including PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 were determined with a SNaPshot method.</p><p><b>RESULTS</b>The P values for the genotype frequencies of rs11024102, rs3753841 and rs1015213 between the patient and control groups were 0.62 (OR=1.09, 95%CI: 0.91-1.30), 0.42 (OR=1.04, 95%CI: 0.87-1.41) and 0.34 (OR=1.35, 95%CI: 0.73-2.49), respectively. And the P values for the allele frequency distributions of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 between the two groups were 0.347, 0.698 and 0.344, respectively.</p><p><b>CONCLUSION</b>No significant association of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 with PACG was found among ethnic Han Chinese from Sichuan.</p>
Subject(s)
Female , Humans , Male , Carrier Proteins , Genetics , China , Ethnology , Collagen Type XI , Genetics , Glaucoma, Angle-Closure , Genetics , Polymorphism, Single Nucleotide , Protein D-Aspartate-L-Isoaspartate Methyltransferase , GeneticsABSTRACT
Objective To study the correlation of 5 polymorphisms of Han Chinese patients in Sichuan Province with age-related macular degeneration (AMD). Methods The blood samples from 384 Han Chinese patients diagnosed with AMD and another 384 matched controls were collected using case-control study method. The chosen gene single nucleotide polymorphisms (SNPs) were genotyped by SnaPShot classify technology in the patients with AMD and 384 controls of Chinese Han population. Results All of the 5 genetype frequencies of the SNPs were in accordance with Hardy-Weinberg Equilibrium (P > 0.05). There were no statistically significantdifferences between the AMD group and the control group in the rs13117504 G allele frequency (P = 0.037, OR=1.24, 95%CI:1.01~1.53), the rs10033900 C allele frequency (P=0.023, OR=1.27, 95%CI: 1.03 ~1.57) and the rs1003390 frequency in the AMD dominant model (P = 0.039, OR = 0.74, 95%CI: 0.55 ~ 0.99). There were no statistically significant differences between the groups in the rs6822976 A allele frequencies (P =0.158), the rs7438961 G allele frequencies (P = 0.798) and, the rs7671905 T allele frequency (P = 0.909). The rs10033900 in the recessive model of AMD had no significant difference as compared to that in the control group (P = 0.107). The two groups showed no significant differences in both the dominant and recessive model of AMD in terms of the frequencies of rs13117504, rs6822976, rs7438961 and rs7671905 (P > 0.05). Conclusion The rs13117504 and rs10033900 of SNPs near CFI gene upstream has significant association with age-related macular degeneration , while the rs6822976 , rs7438961 , rs7671905 of SNPs have no significant correlations with age-related macular degeneration in Han Chinese population.
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Retinitis pigmentosa (RP) is a group of inherited disorders which involve photoreceptors of the retina and can lead to visual loss. The genetic and clinical phenotypes of RP feature high heterogeneity. RP can be divided into nonsyndromic and syndromic types, both may feature autosomal dominant, autosomal reccesive and X-linked inheritance. So far, many genes have been identified, most of which are expressed in the photoreceptors or retinal pigment epithelium. Sixty-three genes have been identified in nonsyndromic RP. This paper reviews recent progress in the research of the genetics of RP.
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Humans , Genes, X-Linked , Proteins , Genetics , Retinitis Pigmentosa , GeneticsABSTRACT
<p><b>INTRODUCTION</b>Retinitis pigmentosa (RP) describes a group of inherited disorders characterised by progressive retinal dysfunction, cell loss and atrophy of retinal tissue. RP demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and identify the disease-causing mutation, and then to describe the phenotypic presentation of this family.</p><p><b>MATERIALS AND METHODS</b>Ophthalmic examination was performed on 46 family members to identify affected individuals and to characterise the disease phenotype. Family pedigree was obtained. Some family members also had fundus photographs, fluorescein angiography, and/or optical coherence tomography (OCT) analysis performed. Genetic linkage was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for autosomal dominant RP. Finally, DNA sequencing was performed to identify the mutation present in this family.</p><p><b>RESULTS</b>Clinical features included nyctalopia, constriction of visual fields and eventual loss of central vision. Sequence analysis revealed a G-to-T nucleotide change in the Rhodopsin gene, predicting a Gly-51-Val substitution.</p><p><b>CONCLUSIONS</b>This large multi-generation family demonstrates the phenotypic variability of a previously identified autosomal dominant mutation of the Rhodopsin gene.</p>
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Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Male , Middle Aged , Genes, Dominant , Mutation , Pedigree , Retinitis Pigmentosa , Genetics , Rhodopsin , GeneticsABSTRACT
<p><b>INTRODUCTION</b>Retinitis pigmentosa (RP) is the most prevalent group of inherited retinopathies and demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and to identify the disease-causing gene/locus.</p><p><b>MATERIALS AND METHODS</b>Ophthalmic examination was performed on 35 family members to identify affected individuals and carriers and to characterise the disease phenotype. Genetic linkage analysis was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for Xlinked RP (xlRP) including RP2, RP3, RP6, RP23, and RP24. Mutation screening was performed by direct sequencing of PCR-amplified genomic DNA of the RP2 and RPGR genes of the affected individuals.</p><p><b>RESULTS</b>A highly penetrant, X-linked form of RP was observed in this family. Age of onset was from 5 to 8 years and visual acuity ranged from 20/25 in children to light perception in older adults. Linkage analysis and direct sequencing showed that no known loci/genes were associated with the phenotype in this kindred.</p><p><b>CONCLUSION</b>A novel disease gene locus/loci is responsible for the xlRP phenotype in this family.</p>
Subject(s)
Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Age of Onset , Chromosome Mapping , DNA Mutational Analysis , Eye Proteins , Genetics , Genetic Diseases, X-Linked , Genetics , Intracellular Signaling Peptides and Proteins , Genetics , Lod Score , Membrane Proteins , Genetics , Pedigree , Phenotype , Retinitis Pigmentosa , GeneticsABSTRACT
Objective To investigate the expression of parathyroid hormone/parathyroid hormone relative protein (PTH/PTHrP) receptor of osteoblast in hemodialysis patients and the effects of calcium channel blocker(CCB) and calcitriol on it. Methods Twenty-one patients on HD were randomly divided into three groups. Six patients were treated with CCB for 8 weeks. Seven patients were given calcitriol for 8 weeks. The rest 8 cases did not take either CCB or calcitriol. Five healthy people were selected as control group. The serum levels of iPTH, BUN, Scr, calcium and phosphorus were measured. The osteoblast was prepared from cultured bone marrow. PTH receptor mRNA expression was detected by semi-quantitive RT-PCR. Results The level of PTH/PTHrP receptor mRNA decreased significantly in patients on HD as compared with control group, and increased in patients with CCB. In calcitriol treated group, and PTH/PTHrP receptor was obviously down-regulated with larger dose of calcitriol(0. 75?g/d), and up-regulated with low dose(0. 25?g/d) . Conclusion Expression of PTH/PTHrP receptor down-regulates in osteoblast of HD patients. CCB can up-regulate the expression of PTH/PTHrP receptor. A large dose of calcitriol may decrease iPTH level and down-regulate PTH/PTHrP receptor expression.