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1.
Hum Genet ; 138(10): 1077-1090, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31172260

RESUMO

High hyperopia is a common and severe form of refractive error. Genetic factors play important roles in the development of high hyperopia but the exact gene responsible for this condition is mostly unknown. We identified a large Chinese family with autosomal dominant high hyperopia. A genome-wide linkage scan mapped the high hyperopia to chromosome 11p12-q13.3, with maximum log of the odds scores of 4.68 at theta = 0 for D11S987. Parallel whole-exome sequencing detected a novel c.3377delG (p.Gly1126Valfs*31) heterozygous mutation in the MYRF gene within the linkage interval. Whole-exome sequencing in other 121 probands with high hyperopia identified additional novel mutations in MYRF within two other families: a de novo c.3274_3275delAG (p.Leu1093Profs*22) heterozygous mutation and a c.3194+2T>C heterozygous mutation. All three mutations are located in the C-terminal region of MYRF and are predicted to result in truncation of that portion. Two patients from two of the three families developed angle-closure glaucoma. These three mutations were present in neither the ExAC database nor our in-house whole-exome sequencing data from 3280 individuals. No other truncation mutations in MYRF were detected in the 3280 individuals. Knockdown of myrf resulted in small eye size in zebrafish. These evidence all support that truncation mutations in the C-terminal region of MYRF are responsible for autosomal dominant high hyperopia in these families. Our results may provide useful clues for further understanding the functional role of the C-terminal region of this critical myelin regulatory factor, as well as the molecular pathogenesis of high hyperopia and its associated angle-closure glaucoma.


Assuntos
Cromossomos Humanos Par 11 , Oftalmopatias Hereditárias/genética , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Hiperopia/genética , Proteínas de Membrana/genética , Mutação , Fatores de Transcrição/genética , Animais , Mapeamento Cromossômico , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Angiofluoresceinografia , Técnicas de Inativação de Genes , Loci Gênicos , Humanos , Hiperopia/diagnóstico , Escore Lod , Masculino , Linhagem , Fenótipo , Peixe-Zebra
2.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
3.
Hum Genet ; 138(6): 673-679, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069506

RESUMO

The study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study. We calculated the gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained an accuracy of 80%, recall of 93% and area under the curve of 0.87. Our results estimated that a total of 10,384 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease. Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.


Assuntos
Algoritmos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Aprendizado de Máquina , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Humanos , Curva ROC
4.
Lipids Health Dis ; 18(1): 105, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31036026

RESUMO

BACKGROUND: Studies had investigated the associations between proprotein convertase subtilisin/kexin type 9 SNP rs562556 and serum lipids levels and response to statin treatment, however, the results remained inconclusive. We conducted this meta-analysis to elucidate the relationship of rs562556 and serum lipids levels. METHODS: All eligible studies met the inclusion criteria were retrieved from multiple databases. Relative data were extracted from each study. Review Manager (version 5.3.5) and STATA 12.0 software was used to perform this meta-analysis. Pooled standardized mean difference (SMD) with 95% CI was employed to evaluate the association of rs562556 with serum lipids levels. RESULTS: A total of 7 eligible articles involving 4742 subjects were included in the final meta-analysis. The results revealed that the G carriers had lower levels of total cholesterol (SMD: 0.14, 95% Cl: 0.06-0.23, P = 0.001) and LDL-C(SMD: 0.13, 95% Cl: -0.55-0.22,P = 0.002) than the non-carriers. The statistical results also illustrated that the G carriers had lower relative risk (SMD: 1.38, 95% Cl: 1.02-1.85, P = 0.003) than the non-carriers. CONCLUSIONS: The results of the current meta-analysis for the first time indicated the relevance of rs562556 and lower serum cholesterol levels.


Assuntos
Estudos de Associação Genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Genes Dominantes , Humanos , Viés de Publicação , Risco
5.
BMC Med Genet ; 20(1): 80, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088393

RESUMO

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.


Assuntos
Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/genética , Mutação , Adolescente , Criança , Pré-Escolar , China , Cromossomos Humanos X , Feminino , Genes Dominantes , Genes Recessivos , Heterogeneidade Genética , Humanos , Lactente , Masculino , Linhagem , Fenótipo
6.
BMC Med Genet ; 20(1): 84, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101089

RESUMO

BACKGROUND: Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal dominant trait caused by a novel EYA4 mutation. CASE PRESENTATION: Forty-four years old female proband clinically investigated for progressive hearing loss and occasional dizziness with positive family history for deafness was subject to molecular-genetic testing. Patient's DNA sample was analyzed by whole exome sequencing. We identified a novel missense variant c.804G > C located at the last base pair of exon 10 in EYA4. Candidate variant was confirmed by Sanger sequencing in the proband and her family members. In silico prediction tools and co-segregation analysis were used to indicate pathogenicity of the identified variant. To confirm our hypothesis, we performed minigene assay to demonstrate if the transcript of exon 10 in EYA4 is present. We provide evidence that this mutation in vitro compromises donor site functionality and causes exon 10 skipping and frameshift that most likely results in nonsense-mediated mRNA decay. The onset of moderate to severe hearing loss in the family ranged from 10 to 40 years. The normal cardiac phenotype was confirmed by ECG and echocardiography. CONCLUSIONS: We identified a novel EYA4 mutation associated with adult-onset autosomal dominant sensorineural hearing loss. This report extends the knowledge of spectrum of EYA4 mutations and demonstrates the pathogenicity of a variant affecting specific position in the gene. A comprehensive review of known EYA4 mutations is also given and their impact on cardiac phenotype is discussed. Our findings highlight the importance of genetic testing and complex clinical assessment in patients with familial progressive hearing loss.


Assuntos
Genes Dominantes , Perda Auditiva/genética , Transativadores/genética , Idade de Início , Feminino , Humanos , Pessoa de Meia-Idade , Eslováquia
7.
Lipids Health Dis ; 18(1): 103, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010439

RESUMO

BACKGROUND: Patients with diabetes mellitus were often accompanied with hyperlipidemia. ATP-binding cassette sub-family A member1 (ABCA1) promotes the efflux of lipids and thereby mediates the metabolism of cholesterol. The aim of our study was to determine the associations of ABCA1 gene polymorphisms with the risks of diabetes mellitus and dyslipidemia in diabetic patients. METHODS: We retrieved literature about the relationship between ABCA1 gene polymorphisms (C69T and R230C) and the risk of diabetes through PubMed, Web of Science, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Cochrane database. Weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively, accompanied by their 95% confidence interval (CI). RESULTS: A total of 1746 diabetic patients and 1292 non-diabetic controls were enrolled. All subjects were Caucasians. ABCA1 R230C T allele was significantly associated with reduced the risk of diabetes (OR = 0.75, 95% CI = 0.57-0.98, P = 0.04). There was no association of ABCA1 C69T gene polymorphisms with the risk of diabetes. However, subgroup analyses showed that the ABCA1 C69T gene mutation significantly reduced the risk of hypertriglyceridemia in diabetic patients as compared with that in non-diabetic subjects (dominant model: WMD =0.66, 95% CI = 0.52-0.8, P < 0.0001; recessive model: WMD = 0.47, 95%CI = 0.11-0.83, P = 0.01). CONCLUSIONS: ABCA1 R230C T allele gene mutation is a protective in decreasing the risk of diabetes in Caucasians and ABCA1 C69T gene mutation markedly influences the level of lipid metabolism in diabetic patients.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Metabolismo dos Lipídeos/genética , Mutação/genética , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Viés de Publicação , Fatores de Risco
8.
Cell Mol Biol (Noisy-le-grand) ; 65(3): 84-88, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30942159

RESUMO

The aim of this study was to identify the novel missense eya4 mutation which cause autosomal dominant non syndromic hearing loss In a Chinese family. Hearing loss is the most common sensory deficit in humans, but the middle-frequency sensorineural hearing loss (MFSNHL) is rare among hereditary non-syndromic hearing loss, and EYA4 is one of the genes reported to be associated with MFSNHL. A genetic analysis of a Chinese family with autosomal dominant non­syndromic progressive hearing impairment was conducted and assessed. Targeted exome sequencing, conducted using DNA samples of an affected member in this family, revealed a novel heterozygous missense mutation c.1855T>G in exon 20 of EYA4, causing amino-acid (aa) substitution Gly for Trp at a conserved position aa-619. The p.W619G mutation related to hearing loss in this Chinese family was validated by Sanger sequencing. Bioinformatic analysis confirmed the pathogenic effects of this mutation. We identified the novel missense mutation c.1855T>G (p.W619G) in EYA4 causing autosomal dominant non-syndromic hearing impairment in the selected Chinese family.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genes Dominantes , Perda Auditiva/genética , Mutação de Sentido Incorreto/genética , Transativadores/genética , Adulto , Idoso , Simulação por Computador , Exoma/genética , Família , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Software
9.
Nat Methods ; 16(5): 413-416, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962621

RESUMO

Dominant negative polypeptides can inhibit protein function by binding to a wild-type subunit or by titrating a ligand. Here we use high-throughput sequencing of libraries composed of fragments of yeast genes to identify polypeptides that act in a dominant negative manner, in that they are depleted during cell growth. The method can uncover numerous inhibitory polypeptides for a protein and thereby define small inhibitory regions, even pinpointing individual residues with critical functional roles.


Assuntos
Genes Dominantes , Genes Fúngicos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Peptídeos/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a DNA/genética , Biblioteca Gênica , Proteínas de Choque Térmico/genética , Proteínas de Saccharomyces cerevisiae/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética
10.
BMC Med Genet ; 20(1): 57, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935366

RESUMO

BACKGROUND: Many mutations in the α-tectorin gene (TECTA) have been reported to cause non-syndromic hearing loss (NSHL) in either a dominant or recessive inheritance pattern. Among the identified TECTA mutations, H1400Y has been associated with NSHL in two independent studies. However, its exact role in contributing to genetic hearing loss remains elusive. CASE PRESENTATION: We herein report the whole-exome sequencing of a proband presenting with prelingual, non-progressive, mild-to-moderate hearing loss in a simplex family. By using trio-based whole-exome sequencing, we found two heterozygous mutations of R1890C and H1400Y in the ZP and ZA domains of TECTA, respectively. R1890C, previously reported as a pathogenic autosomal dominant mutation of genetic hearing loss, was found to be inherited in a de novo pattern, causing hearing loss in the proband. By contrast, H1400Y was not segregated in this family, and one family member with normal hearing also carried the H1400Y mutation. CONCLUSION: According to the hearing loss-specific American College of Medical Genetics and Genomics (ACMG) guidelines, we conclude that H1400Y should be disqualified as a cause of genetic hearing loss. True pathogenic variants causing genetic hearing loss should be more deliberately reported in accordance with ACMG guidelines.


Assuntos
Proteínas da Matriz Extracelular/genética , Perda Auditiva Neurossensorial/genética , Mutação , Pré-Escolar , Feminino , Proteínas Ligadas por GPI/genética , Genes Dominantes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
11.
Mol Vis ; 25: 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820140

RESUMO

Purpose: To identify the mutation for Volkmann cataract (CTRCT8) at 1p36.33. Methods: The genes in the candidate region 1p36.33 were Sanger and parallel deep sequenced, and informative single nucleotide polymorphisms (SNPs) were identified for linkage analysis. Expression analysis with reverse transcription polymerase chain reaction (RT-PCR) of the candidate gene was performed using RNA from different human tissues. Quantitative transcription polymerase chain reaction (qRT-PCR) analysis of the GNB1 gene was performed in affected and healthy individuals. Bioinformatic analysis of the linkage regions including the candidate gene was performed. Results: Linkage analysis of the 1p36.33 CCV locus applying new marker systems obtained with Sanger and deep sequencing reduced the candidate locus from 2.1 Mb to 0.389 Mb flanked by the markers STS-22AC and rs549772338 and resulted in an logarithm of the odds (LOD) score of Z = 21.67. The identified mutation, rs763295804, affects the donor splice site in the long non-coding RNA gene RP1-140A9.1 (ENSG00000231050). The gene including splice-site junctions is conserved in primates but not in other mammalian genomes, and two alternative transcripts were shown with RT-PCR. One of these transcripts represented a lens cell-specific transcript. Meta-analysis of the Cross-Linking-Immuno-Precipitation sequencing (CLIP-Seq) data suggested the RNA binding protein (RBP) eIF4AIII is an active counterpart for RP1-140A9.1, and several miRNA and transcription factors binding sites were predicted in the proximity of the mutation. ENCODE DNase I hypersensitivity and histone methylation and acetylation data suggest the genomic region may have regulatory functions. Conclusions: The mutation in RP1-140A9.1 suggests the long non-coding RNA as the candidate cataract gene associated with the autosomal dominant inherited congenital cataract from CCV. The mutation has the potential to destroy exon/intron splicing of both transcripts of RP1-140A9.1. Sanger and massive deep resequencing of the linkage region failed to identify alternative candidates suggesting the mutation in RP1-140A9.1 is causative for the CCV phenotype.


Assuntos
Catarata/congênito , Cromossomos Humanos Par 1/química , Mutação , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Acetilação , Adulto , Sequência de Bases , Sítios de Ligação , Catarata/diagnóstico , Catarata/genética , Catarata/patologia , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Éxons , Família , Feminino , Genes Dominantes , Loci Gênicos , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/genética , Histonas/metabolismo , Humanos , Íntrons , Masculino , Metilação , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA , Processamento de RNA , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo
12.
Methods Mol Biol ; 1957: 69-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30919347

RESUMO

Arrestin proteins were originally characterized as regulators of GPCR desensitization, and that function alone was sufficient to promote extreme interest in their study. It is now appreciated that arrestins also function as mediators of GPCR trafficking and G protein-independent signaling. This latter function places them as prominent players in the emerging field of qualitative signaling, which promises to launch a new area of pharmacology that defines ligands with selectivity/bias toward either G protein-dependent or -independent signaling. To meet the demands of research into arrestin function, methodology has evolved accordingly over the last three decades since the discovery of the arrestin family. Herein we describe state-of-the-art approaches for studying the role of arrestins (ß-arrestin1 aka arrestin 2, ß-arrestin2 aka arrestin 3) in GPCR function in a primary cell type, cultured airway smooth muscle cells.


Assuntos
Biologia Molecular/métodos , Músculo Liso/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Respiratório/metabolismo , beta-Arrestinas/metabolismo , Genes Dominantes , Humanos , RNA Interferente Pequeno/metabolismo , Retroviridae/metabolismo
13.
Comput Math Methods Med ; 2019: 6216530, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863455

RESUMO

Background: Alzheimer's disease (AD) is a major public health concern, and there is an urgent need to better understand its complex biology and develop effective therapies. AD progression can be tracked in patients through validated imaging and spinal fluid biomarkers of pathology and neuronal loss. We still, however, lack a coherent quantitative model that explains how these biomarkers interact and evolve over time. Such a model could potentially help identify the major drivers of disease in individual patients and simulate response to therapy prior to entry in clinical trials. A current theory of AD biomarker progression, known as the dynamic biomarker cascade model, hypothesizes AD biomarkers evolve in a sequential but temporally overlapping manner. A computational model incorporating assumptions about the underlying biology of this theory and its variations would be useful to test and refine its accuracy with longitudinal biomarker data from clinical trials. Methods: We implemented a causal model to simulate time-dependent biomarker data under the descriptive assumptions of the dynamic biomarker cascade theory. We modeled pathologic biomarkers (beta-amyloid and tau), neuronal loss biomarkers, and cognitive impairment as nonlinear first-order ordinary differential equations (ODEs) to include amyloid-dependent and nondependent neurodegenerative cascades. We tested the feasibility of the model by adjusting its parameters to simulate three specific natural history scenarios in early-onset autosomal dominant AD and late-onset AD and determine whether computed biomarker trajectories agreed with current assumptions of AD biomarker progression. We also simulated the effects of antiamyloid therapy in late-onset AD. Results: The computational model of early-onset AD demonstrated the initial appearance of amyloid, followed by biomarkers of tau and neurodegeneration and the onset of cognitive decline based on cognitive reserve, as predicted by the prior literature. Similarly, the late-onset AD computational models demonstrated the first appearance of amyloid or nonamyloid-related tauopathy, depending on the magnitude of comorbid pathology, and also closely matched the biomarker cascades predicted by the prior literature. Forward simulation of antiamyloid therapy in symptomatic late-onset AD failed to demonstrate any slowing in progression of cognitive decline, consistent with prior failed clinical trials in symptomatic patients. Conclusions: We have developed and computationally implemented a mathematical causal model of the dynamic biomarker cascade theory in AD. We demonstrate the feasibility of this model by simulating biomarker evolution and cognitive decline in early- and late-onset natural history scenarios, as well as in a treatment scenario targeted at core AD pathology. Models resulting from this causal approach can be further developed and refined using patient data from longitudinal biomarker studies and may in the future play a key role in personalizing approaches to treatment.


Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Simulação por Computador , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides , Teorema de Bayes , Ensaios Clínicos como Assunto , Disfunção Cognitiva , Progressão da Doença , Genes Dominantes , Humanos , Estudos Longitudinais , Modelos Teóricos , Neurônios/patologia , Reprodutibilidade dos Testes , Fatores de Tempo
14.
Theor Appl Genet ; 132(7): 1953-1963, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30895332

RESUMO

Spot form net blotch (SFNB) caused by the necrotrophic fungal pathogen Pyrenophora teres f. maculata (Ptm) is an important disease of barley worldwide including the major barley production regions of North America. To characterize SFNB resistance/susceptibility quantitative trait loci (QTL), three recombinant inbred line (RIL) populations were developed from crosses between the malting barley cultivars, Tradition (six row) and Pinnacle (two row), and the two world barley core collection lines, PI67381 and PI84314. Tradition and Pinnacle were susceptible to many North American Ptm isolates, while PI67381 and PI84314 carry resistances to diverse Ptm isolates from across the globe. The RIL populations, Tradition/PI67381, Pinnacle/PI67381, and Pinnacle/PI84314 were genotyped using polymerase chain reaction-mediated genotype-by-sequencing single nucleotide polymorphism marker panels and phenotyped at the seedling stage with six geographically distinct Ptm isolates: FGOB10Ptm-1 (North Dakota, USA), Pin-A14 (Montana, USA), Cel-A17 (Montana, USA), SG1 (Australia), NZKF2 (New Zealand) and DEN2.6 (Denmark). The goal was to determine if the susceptible elite lines contained common susceptibility genes/QTL or if the resistant lines had common resistant genes/QTL effective against diverse Ptm isolates. The QTL analyses identified a total of 12 resistance and/or susceptibility loci on chromosomes 2H, 3H, 4H, 6H, and 7H of which three had not been previously reported. Common major QTL were detected on chromosome 2H (R2 = 14-40%) and 7H (R2 = 24-80%) in all three RIL populations, suggesting underlying genes with broad resistance specificity. The major 7H QTL was shown to be a dominant susceptibility gene in both susceptible malting barley varieties.


Assuntos
Resistência à Doença/genética , Hordeum/genética , Doenças das Plantas/genética , Locos de Características Quantitativas , Ascomicetos/patogenicidade , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Cruzamentos Genéticos , Genes Dominantes , Genes de Plantas , Genótipo , Hordeum/microbiologia , Fenótipo , Doenças das Plantas/microbiologia , Polimorfismo de Nucleotídeo Único
15.
Dis Model Mech ; 12(3)2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30923190

RESUMO

Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB). Knockdown flies were tested for defects in MB morphology, short-term memory and long-term memory. Using this approach, we identified distinct roles for individual subunits of the Drosophila SWI/SNF complex. Bap60, Snr1 and E(y)3 are required for pruning of the MBγ neurons during pupal morphogenesis, while Brm and Osa are required for survival of MBγ axons during ageing. We used the courtship conditioning assay to test the effect of MB-specific SWI/SNF knockdown on short- and long-term memory. Several subunits, including Brm, Bap60, Snr1 and E(y)3, were required in the MB for both short- and long-term memory. In contrast, Osa knockdown only reduced long-term memory. Our results suggest that individual components of the SWI/SNF complex have different roles in the regulation of structural plasticity, survival and functionality of post-mitotic MB neurons. This study highlights the many possible processes that might be disrupted in SWI/SNF-related ID disorders. Our broad phenotypic characterization provides a starting point for understanding SWI/SNF-mediated gene regulatory mechanisms that are important for development and function of post-mitotic neurons.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Drosophila melanogaster/metabolismo , Memória , Corpos Pedunculados/inervação , Corpos Pedunculados/metabolismo , Fatores de Transcrição/metabolismo , Envelhecimento/metabolismo , Animais , Corte , Proteínas de Drosophila/metabolismo , Feminino , Genes Dominantes , Deficiência Intelectual/genética , Masculino , Morfogênese , Plasticidade Neuronal
16.
Biomed Res ; 40(1): 37-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787262

RESUMO

The tumor suppressor gene TP53 (gene) codes for a transcription factor which transactivates its target genes responsible for cell cycle arrest, DNA repair, apoptosis, and senescence. TP53 is well known to be the most frequent target of genetic mutations in nearly half of human cancers including oral squamous cell carcinoma (OSCC). Many p53 mutants including R248Q and R248W not only lose its tumor-suppressor activities, but also interfere with the functions of wild-type p53; this is so-called dominant-negative (DN) mutation. The DN p53 mutation is a predictor of poor outcome in patients with various cancers, and also a risk factor for metastatic recurrence in patients with OSCC. Recently it has been reported that DN p53 mutants acquire new oncogenic activities, which is named gain-of-function (GOF). This study aimed at determining whether R248Q and R248W were involved in OSCC cells' acquiring aggressive phenotypes, using SAS, HSC4 and Ca9-22 cell lines. First, two mutants p53, R248Q and R248W, were respectively transfected into SAS cells harboring recessive-type p53 (E336X). As a result, SAS cells expressing R248Q showed highly spreading, motile and invasive activities compared to parent or mock-transfected cells whereas those expressing R248W did not increase those activities. Secondly, in HSC4 cells harboring R248Q and Ca9-22 cells harboring R248W, expressions of the mutants p53 were inhibited by the transfection with siRNAs targeting p53. The inhibition of the mutants p53 decreased spreading, motile and invasive activities of HSC4 cells whereas it did not affect those activities of Ca9-22 cells. These findings suggest that R248Q p53 mutation, but not R248W p53 mutation, induces more motile and invasive potentials in human OSCC cells.


Assuntos
Alelos , Substituição de Aminoácidos , Movimento Celular/genética , Genes Dominantes , Mutação , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Carcinoma de Células Escamosas/genética , Adesão Celular/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Matriz Extracelular/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Neoplasias Bucais/genética , Ligação Proteica , RNA Interferente Pequeno/genética , Elementos de Resposta , Proteína Supressora de Tumor p53/metabolismo
17.
J Neurol ; 266(4): 934-941, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706156

RESUMO

BACKGROUND: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations. METHODS: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing. RESULTS: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation. CONCLUSIONS: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.


Assuntos
Contratura/genética , Distrofias Musculares/congênito , Mutação , Adulto , Idoso , Colágeno Tipo VI/genética , Contratura/diagnóstico por imagem , Contratura/patologia , Creatina Quinase/metabolismo , Feminino , Seguimentos , Genes Dominantes , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/genética , Distrofias Musculares/patologia , Fenótipo , Estudos Retrospectivos , Adulto Jovem
18.
Mamm Genome ; 30(3-4): 81-87, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30788588

RESUMO

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I (COL1A1), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it was absent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.


Assuntos
Doenças dos Bovinos/genética , Mutação em Linhagem Germinativa , Osteogênese Imperfeita/veterinária , Alelos , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Feminino , Genes Dominantes , Masculino , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , Linhagem , Fenótipo
19.
Stem Cell Res ; 34: 101357, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611018

RESUMO

We report the generation of the human iPSC line LEIi008-A from a patient with retinitis pigmentosa-11 caused by a dominant nonsense mutation in the PRPF31 gene (NM_015629.3:c.1205C > A p.(Ser402Ter)). A second line, LEIi009-A, was generated from a related non-penetrant carrier of the same mutation with no retinal disease. Reprogramming of patient dermal fibroblasts using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, shRNA for p53 and mir302/367 microRNA generated cell lines displaying pluripotent stem cell marker expression, a normal karyotype and the capability to differentiate into the three germ layer lineages. Resource table.


Assuntos
Técnicas de Cultura de Células/métodos , Proteínas do Olho/genética , Genes Dominantes , Células-Tronco Pluripotentes Induzidas/patologia , Mutação/genética , Penetrância , Adolescente , Adulto , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Theor Appl Genet ; 132(4): 1283-1294, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666393

RESUMO

KEY MESSAGE: The nematode resistance gene H2 was mapped to the distal end of chromosome 5 in tetraploid potato. The H2 resistance gene, introduced into cultivated potatoes from the wild diploid species Solanum multidissectum, confers a high level of resistance to the Pa1 pathotype of the potato cyst nematode Globodera pallida. A cross between tetraploid H2-containing breeding clone P55/7 and susceptible potato variety Picasso yielded an F1 population that segregated approximately 1:1 for the resistance phenotype, which is consistent with a single dominant gene in a simplex configuration. Using genome reduction methodologies RenSeq and GenSeq, the segregating F1 population enabled the genetic characterisation of the resistance through a bulked segregant analysis. A diagnostic RenSeq analysis of the parents confirmed that the resistance in P55/7 cannot be explained by previously characterised resistance genes. Only the variety Picasso contained functionally characterised disease resistance genes Rpi-R1, Rpi-R3a, Rpi-R3b variant, Gpa2 and Rx, which was independently confirmed through effector vacuum infiltration assays. RenSeq and GenSeq independently identified sequence polymorphisms linked to the H2 resistance on the top end of potato chromosome 5. Allele-specific KASP markers further defined the locus containing the H2 gene to a 4.7 Mb interval on the distal short arm of potato chromosome 5 and to positions that correspond to 1.4 MB and 6.1 MB in the potato reference genome.


Assuntos
Mapeamento Cromossômico , Resistência à Doença/genética , Solanum tuberosum/genética , Solanum tuberosum/parasitologia , Tetraploidia , Tylenchoidea/patogenicidade , Animais , Segregação de Cromossomos/genética , Cromossomos de Plantas/genética , Cruzamentos Genéticos , Genes Dominantes , Genes de Plantas , Loci Gênicos , Proteínas NLR/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/parasitologia , Polimorfismo de Nucleotídeo Único/genética , Solanum tuberosum/imunologia
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