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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(11): 1101-1105, 2021 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-34729752

RESUMO

OBJECTIVE: To analyze the phenotype and genetic variant in a pedigree affected with inherited protein C (PC) deficiency. METHODS: The proband and her family members (7 individuals from 3 generations) were tested for plasma protein C activity (PC:A), protein C antigen (PC:Ag) content and other coagulation indicators. All of the 9 exons and flanking sequences of the proband's PROC gene were amplified by PCR and sequenced. Suspected variants were verified by reverse sequencing of the proband and her family members. Bioinformatic software was used to analyze the pathogenicity and conservation of the variant site. Swiss-PdbViewer was used to analyze the three-dimensional model and the interaction with the mutant amino acid. RESULTS: The PC:A and PC:Ag of the proband, her grandmother, father and elder brother were decreased to 55%, 52%, 48%, 51% and 53%, 55%, 50%, 56%, respectively. Genetic analysis showed that the four individuals have all carried heterozygous c.1318C>T (p.Arg398Cys) missense mutation in exon 9 of the PROC gene. The score of MutationTaster was 0.991, PROVEAN was -3.72, and FATHMM was -2.49, all predicted it to be a harmful mutation. Phylogenetic analysis also showed that Arg398 was weakly conservative among homologous species. Protein model analysis showed that, in the wild type, Arg398 can form a hydrogen bond with Glu341 and Lys395 respectively, when it was mutated to Cys398, the hydrogen bond with Glu341 disappears and an additional hydrogen bond was formed with Lys395, which has changed the spatial structure of the protein. CONCLUSION: The heterozygous missense mutation c.1318C>T (p.Arg398Cys) of the PROC gene probably underlay the decreased PC:A and PC:Ag in this pedigree.


Assuntos
Deficiência de Proteína C , Idoso , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Filogenia , Deficiência de Proteína C/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(11): 1110-1113, 2021 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-34729754

RESUMO

OBJECTIVE: To provide a basis for genetic counseling and clinical precision therapy by exploring the genetic etiology of a child with recurrent hypoglycemia convulsion accompanied by language retardation. METHODS: Peripheral blood samples were obtained from the proband, his sister and his parents. Whole genomic DNA was extracted and analyzed by the whole exon gene sequencing and confirmed by Sanger sequencing. RESULTS: The proband and his sister were found to carry compound heterozygous variants c.731T>A (p.M244L) and c.928G>A (p.G244S) of the GYS2 gene, which had not been reported in the past, the c.731T>A (p.M244L) site was derived from the maternal heterozygous mutation, while c.928G>A (p.G244S) site from the father heterozygous mutation. CONCLUSION: The compound heterozygous variants c.731T>A (p.M244L) and c.928G>A (p.G244S) of the GYS2 gene were the genetic cause of glycogen storage syndrome type 0 in children, providing basis for family genetic counseling. When the patient had Hypoglycemia often accompanied with convulsions, which was easy to be misdiagnosed as seizures, and the antiepileptic treatment was ineffective. After genetic diagnosis, the seizure can be controlled by improving diet to maintain blood glucose stability.


Assuntos
Glicogênio , Irmãos , Criança , Éxons , Heterozigoto , Humanos , Mutação , Linhagem
3.
Invest Ophthalmol Vis Sci ; 62(14): 3, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34727153

RESUMO

Purpose: Birdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers. Methods: We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29-positive controls to determine genome-wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk. Results: Carrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, -A30, -A31, and -A33) increases the risk for BSCR (odds ratio [OR] = 4.44; P = 2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n = 45,386; OR > 2.5; P < 1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate disease risk. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR = 2.46; 95% confidence interval [CI], 1.85-3.26; P = 4.07e-10), an expression quantitative trait locus (eQTL) decreasing ERAP1 expression; and ERAP2-rs10044354 (OR = 1.95; 95% CI, 1.55-2.44; P = 6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR = 0.56; 95% CI, 0.45-0.70; P = 2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR = 13.53; 95% CI, 3.79-54.77; P = 1.17e-05). Conclusions: The genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2-specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.


Assuntos
Aminopeptidases/genética , Coriorretinopatia de Birdshot/genética , Antígenos HLA-A/genética , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único , Alelos , Coriorretinopatia de Birdshot/diagnóstico , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Haplótipos , Heterozigoto , Humanos , Reação em Cadeia da Polimerase Multiplex , Razão de Chances , Fatores de Risco
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(11): 1123-1126, 2021 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-34729757

RESUMO

OBJECTIVE: To explore the genetic basis for a child with 46,XY disorders of sex development (DSD) and explore its genotype-phenotype correlation. METHODS: The child was subjected to whole exome sequencing (WES), and exons 1 to 7 of NR5A1 were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: The patient presented with rudimentary vulva of a female with Tanner stage 1. B-mode ultrasonography has detected ovary and uterus. The child was found to have a chromosome karyotype of 46,XY. WES revealed that the patient has harbored heterozygous deletion of exon 5 of the NR5A1 gene, which was a novel pathogenic variant inherited from the mother. No abnormality was found in the father. CONCLUSION: The main symptoms of 46,XY DSD children are insufficient external genitalia masculinization, for which variants of the NR5A1 gene are an important cause. WES has improved the detection rate of genetic variants and provided a solid basis for genetic counseling of the affected families.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Transtornos do Desenvolvimento Sexual , Criança , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/genética , Éxons/genética , Feminino , Testes Genéticos , Heterozigoto , Humanos , Mutação , Fator Esteroidogênico 1/genética
5.
Am J Hum Genet ; 108(11): 2130-2144, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34653363

RESUMO

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Genes Dominantes , Hexosiltransferases/genética , Proteínas de Membrana/genética , Doenças Musculoesqueléticas/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Domínio Catalítico , Pré-Escolar , Feminino , Heterozigoto , Hexosiltransferases/química , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Linhagem , Homologia de Sequência de Aminoácidos
6.
Am J Hum Genet ; 108(11): 2099-2111, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34678161

RESUMO

The integration of genomic data into health systems offers opportunities to identify genomic factors underlying the continuum of rare and common disease. We applied a population-scale haplotype association approach based on identity-by-descent (IBD) in a large multi-ethnic biobank to a spectrum of disease outcomes derived from electronic health records (EHRs) and uncovered a risk locus for liver disease. We used genome sequencing and in silico approaches to fine-map the signal to a non-coding variant (c.2784-12T>C) in the gene ABCB4. In vitro analysis confirmed the variant disrupted splicing of the ABCB4 pre-mRNA. Four of five homozygotes had evidence of advanced liver disease, and there was a significant association with liver disease among heterozygotes, suggesting the variant is linked to increased risk of liver disease in an allele dose-dependent manner. Population-level screening revealed the variant to be at a carrier rate of 1.95% in Puerto Rican individuals, likely as the result of a Puerto Rican founder effect. This work demonstrates that integrating EHR and genomic data at a population scale can facilitate strategies for understanding the continuum of genomic risk for common diseases, particularly in populations underrepresented in genomic medicine.


Assuntos
Atenção à Saúde/organização & administração , Predisposição Genética para Doença , Hepatopatias/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Registros Eletrônicos de Saúde , Haplótipos , Heterozigoto , Hispano-Americanos/genética , Homozigoto , Humanos , Porto Rico
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 937-941, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625927

RESUMO

OBJECTIVE: To explore the genetic basis of three families with recurrence of non-immune hydrops fetalis (NIHF) but negative result by copy number variation sequencing (CNV-seq). METHODS: Amniotic fluid sample and/or abortive tissues of the fetuses were collected and subjected to CNV-seq analysis. Peripheral blood samples of the parents were also taken for trio whole exome sequencing (trio WES). RESULTS: Fetus 1 was found to harbor heterozygous c.976G>T(p.Glu326*) variant of the SOX18 gene in addition with compound heterozygous variants c.844C>T(p.Arg282Trp) and c.9472+1G>A of the RYR1 gene. The three variants were all inherited from its parents and have been associated with the etiology of NIHF. Based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, the c.976G>T variant of SOX18 gene and c.9472+1G>A of RYR1 gene were predicted to be pathogenic (PVS1+PM2+PP3+PP4, PVS1+PM2+PP3), and c.844C>T variant of RYR1 gene to be likely pathogenic (PM1+PM2+PP3). Fetus 2 was found to harbor compound heterozygous variants c.6682C>T(p.Gln2228*) and c.4373_4383del(p.Val1458Alafs*63) of the PIEZO1 gene. Both variants were also inherited from its parents and are associated with the etiology of NIHF. Based on ACMG standards and guidelines, both c.6682C>T and c.4373_4383del variants of PIEZO1 gene were predicted to be pathogenic (PVS1+PM2+PP4, PVS1+PM2). Fetus 3 was found to harbor compound heterozygous variants of the TTN gene c.29860G>C(p.Asp9954His) and c.21107A>T(p.Asp7036Val), which were respectively inherited from its parents. Both variants have been strongly associated with the phenotype, though the connection between the etiology of NIHF and variants of the TTN gene remains elusive. Based on ACMG standards and guidelines, the c.29860G>C and c.21107A>T variants of TTN gene were predicted to be likely pathogenic (PM1+PM2+PP3). CONCLUSION: Trio WES can improve the diagnosis rate of NIHF with a negative result by CNV-seq. Considering the urgency of prenatal diagnosis, CNV-seq and trio WES should be carried out at the same time for fetuses with NIHF.


Assuntos
Variações do Número de Cópias de DNA , Hidropisia Fetal , Feminino , Genômica , Heterozigoto , Humanos , Hidropisia Fetal/genética , Canais Iônicos , Gravidez , Fatores de Transcrição SOXF , Estados Unidos , Sequenciamento Completo do Exoma
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 951-954, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625930

RESUMO

OBJECTIVE: To explore the genetic basis for a pedigree affected with congenital sensorineural deafness. METHODS: High-throughput sequencing was carried out to analyze the coding regions of 415 genes associated with hereditary deafness in the proband. Suspected variants were verified by PCR amplification and Sanger sequencing of her parents and sister. RESULTS: The proband was found to have carried a heterozygous c.5131G>A (p.Val1711Ile) variant of the CDH23 gene and a heterozygous c.2884C>T(p.Arg962Cys) variant of the PCDH15 gene, which were respectively inherited from her mother and father. Her sister (with normal hearing) was also heterozygous for the c.5131G>A (p.Val1711Ile) variant of the CDH23 gene but not the c.2884C>T (p.Arg962Cys) variant of the PCDH15 gene. Based on the guidelines of the American College of Medical Genetics and Genomics, both variants were predicted to be likely pathogenic (PS1+PM2+PP3+PP4). CONCLUSION: The c.5131G>A (p.Val1711Ile) variant of the CDH23 gene and c.2884C>T (p.Arg962Cys) variant of the PCDH15 gene probably underlay the pathogenesis of Usher syndrome type 1D/F in this pedigree.


Assuntos
Síndromes de Usher , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Linhagem , Síndromes de Usher/genética
9.
Hum Genet ; 140(11): 1517-1523, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34599367

RESUMO

Hair length can be a highly variable trait within the Felis catus species, varying between and within different cat breeds. Previous research has demonstrated this variability is due to recessive mutations within the fibroblast growth factor 5 (FGF5) gene. Following a genetic screen, four longhaired Maine Coons were identified that had only one copy of a known FGF5 mutation. We performed DNA sequencing on samples from two of these Maine Coons and identified a missense mutation in FGF5 c.577G > A p.Ala193Thr. Genetic screening via restriction digest was then performed on samples from the other two Maine Coons and an additional 273 cats of various breeds. This screening found that only the two additional Maine Coons were heterozygous for the novel variant. Furthermore, the novel variant was not identified after in silico analysis of 68 whole genome cat sequences from various breeds, demonstrating that this novel mutation is most likely a breed-specific variant for the Maine Coon, contributing to the longhair phenotype in about 3% of these cats.


Assuntos
Pelo Animal/anatomia & histologia , Gatos/genética , Fator 5 de Crescimento de Fibroblastos/genética , Mutação de Sentido Incorreto , Animais , Gatos/anatomia & histologia , Feminino , Fator 5 de Crescimento de Fibroblastos/química , Heterozigoto , Masculino , Linhagem
10.
BMC Neurol ; 21(1): 402, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34666706

RESUMO

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants. CASE PRESENTATION: A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A). CONCLUSIONS: In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.


Assuntos
Doença de Charcot-Marie-Tooth , Adulto , Doença de Charcot-Marie-Tooth/genética , China , Heterozigoto , Humanos , Masculino , Mutação/genética , Fenótipo , RNA Polimerase III , Adulto Jovem
11.
BMC Pediatr ; 21(1): 442, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625039

RESUMO

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases with clinical and genetic heterogeneity, and CDG-IIg is one of the rare reported types of CDG. The aim of this study is to report the clinical manifestations and gene-phenotype characteristics of a rare case of CDG caused by a COG1 gene mutation and review literatures of CDG disease. CASE PRESENTATION: The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg. We treated the patient with glucose infusion and he was recovered from hypoglycemia. Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father. The genes interacting with COG1 were mainly involved in the transport and composition of the Golgi. The clinical data and laboratory results from a patient diagnosed with CDG-IIg were analyzed, and the causative gene mutation was identified by high-throughput sequencing. The genes and signal pathways related to COG1 were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. CONCLUSIONS: The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg. Because of the various manifestations of CDG in clinical practice, multidisciplinary collaboration is important for the diagnosis and treatment of this disease.


Assuntos
Defeitos Congênitos da Glicosilação , Hipoglicemia , Proteínas Adaptadoras de Transporte Vesicular/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Complexo de Golgi , Heterozigoto , Humanos , Hipoglicemia/genética , Masculino , Mutação
12.
Lancet Oncol ; 22(11): 1618-1631, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34678156

RESUMO

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/sangue , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética
13.
Pediatrics ; 148(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34686572

RESUMO

Our understanding of inflammatory bowel disease is changing as we identify genetic variants associated with immune dysregulation. Inflammatory bowel disease undetermined, even when diagnosed in older children and adolescents, in the setting of multiple inflammatory and infectious diseases should raise the suspicion of complex immune dysregulation with a monogenic basis. We report a case of inflammatory bowel disease undetermined triggered by exposure to a nonsteroidal antiinflammatory drug in a 16-year-old girl with a background history of juvenile idiopathic arthritis, cytopenias, recurrent respiratory tract and middle ear infections, and esophageal candidiasis. Immunologic assessment included measurement of immunoglobulin levels, lymphocyte immunophenotyping, B-cell functional tests, and whole-exome sequencing. Laboratory investigation revealed defects of humoral immunity, including mild persistent hypogammaglobulinemia affecting all 3 isotypes and absent isohemagglutinins. Whole exome sequencing revealed a heterozygous TNFRSF13B (Tumor Necrosis Factor Receptor Superfamily Member 13B, or Transmembrane Activator and Calcium-modulating cyclophilin ligand Interactor, TACI) gene variant, which is associated with common variable immunodeficiency and the development of autoimmune diseases. In conclusion, a clinical history of recurrent infections, atypical histologic features of inflammatory bowel disease, additional autoimmune manifestations, and an inadequate response to conventional therapy should prompt the physician to refer to an immunologist with the query of inborn error of immunity. We report how extensive immune evaluation and genetic diagnosis can individualize care and facilitate a multidisciplinary team approach.


Assuntos
Doenças Autoimunes/genética , Doenças Inflamatórias Intestinais/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adolescente , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite Juvenil/diagnóstico , Doenças Autoimunes/imunologia , Celecoxib/efeitos adversos , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Feminino , Heterozigoto , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/imunologia , Sequenciamento Completo do Exoma
14.
BMC Ophthalmol ; 21(1): 360, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635090

RESUMO

BACKGROUND: To explore the molecular genetic cause of a four-generation autosomal dominant retinitis pigmentosa family in China. METHODS: Targeted region sequencing was performed to detect the potential mutation, and Sanger sequencing was used to validate the mutation. Multiple sequence alignment from different species was performed by CLUSTALW. The structures of wild-type and the mutant RHO were modeled by Swiss-Model Server and shown using a PyMOL Molecular Graphic system. RESULTS: A novel heterozygous nonsense mutation (c.1015 A > T, p.Lys339Ter, p.K339X) within RHO, which cosegregated with retinitis pigmentosa phenotype was detected in this family. Bioinformatics analysis showed the mutation was located in a highly conserved region, and the mutation was predicted to be pathogenic. CONCLUSIONS: We identified a novel heterozygous nonsense mutation of RHO gene in a Chinese family with retinitis pigmentosa by target region sequencing and our bioinformatics analysis indicated that the mutation is pathogenic. Our results can broaden the spectrum of RHO gene mutation and enrich the phenotype-genotype correlation of retinitis pigmentosa.


Assuntos
Códon sem Sentido , Retinite Pigmentosa , China/epidemiologia , Heterozigoto , Humanos , Linhagem , Retinite Pigmentosa/genética
15.
Cell Mol Life Sci ; 78(19-20): 6709-6719, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34559254

RESUMO

Eukaryotic initiation factor (eIF) 4F plays a central role in the ribosome recruitment phase of cap-dependent translation. This heterotrimeric complex consists of a cap binding subunit (eIF4E), a DEAD-box RNA helicase (eIF4A), and a large bridging protein (eIF4G). In mammalian cells, there are two genes encoding eIF4A (eIF4A1 and eIF4A2) and eIF4G (eIF4G1 and eIF4G3) paralogs that can assemble into eIF4F complexes. To query the essential nature of the eIF4F subunits in normal development, we used CRISPR/Cas9 to generate mouse strains with targeted ablation of each gene encoding the different eIF4F subunits. We find that Eif4e, Eif4g1, and Eif4a1 are essential for viability in the mouse, whereas Eif4g3 and Eif4a2 are not. However, Eif4g3 and Eif4a2 do play essential roles in spermatogenesis. Crossing of these strains to the lymphoma-prone Eµ-Myc mouse model revealed that heterozygosity at the Eif4e or Eif4a1 loci significantly delayed tumor onset. Lastly, tumors derived from Eif4e∆38 fs/+/Eµ-Myc or Eif4a1∆5 fs/+/Eµ-Myc mice show increased sensitivity to the chemotherapeutic agent doxorubicin, in vivo. Our study reveals that eIF4A2 and eIF4G3 play non-essential roles in gene expression regulation during embryogenesis; whereas reductions in eIF4E or eIF4A1 levels are protective against tumor development in a murine Myc-driven lymphoma setting.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Fator de Iniciação 4F em Eucariotos/genética , Animais , Feminino , Regulação da Expressão Gênica/genética , Heterozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subunidades Proteicas/genética , Espermatogênese/genética
16.
Stem Cell Res ; 56: 102536, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34536661

RESUMO

A typical DYT1 dystonia is caused by a heterozygous GAG deletion (c.907-909) in the TOR1A gene (ΔE, p.Glu303del) and the pathogenesis is not clear. In this study, human induced pluripotent stem cell (hiPSC) lines carrying the heterozygous or homozygous GAG deletion in TOR1A gene were generated by genetic modification of a healthy hiPSC line (WTC11, UCSFi001-A). These hiPSC lines showed the normal stem cell morphology and karyotype, expressed the same pluripotency markers as their parental line, and had the capacity to differentiate into three germ layers, providing a valuable resource in determining the pathogenesis of human DYT1 dystonia.


Assuntos
Células-Tronco Pluripotentes Induzidas , Heterozigoto , Homozigoto , Humanos , Chaperonas Moleculares/genética , Mutação
17.
PLoS One ; 16(9): e0257974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582500

RESUMO

Sichuan, China, has abundant genetic resources of sheep (Ovis aries). However, their genetic diversity and population structure have been less studied, especially at the genome-wide level. In the present study, we employed the specific-locus amplified fragment sequencing for identifying genome-wide single nucleotide polymorphisms (SNPs) among five breeds of sheep distributed in Sichuan, including three local pure breeds, one composite breed, and one exotic breed of White Suffolk. From 494 million clean paired-end reads, we obtained a total of 327,845 high-quality SNPs that were evenly distributed among all 27 chromosomes, with a transition/transversion ratio of 2.56. Based on this SNP panel, we found that the overall nucleotide diversity was 0.2284 for all five breeds, with the highest and lowest diversity observed in Mage sheep (0.2125) and Butuo Black (0.1963) sheep, respectively. Both Wright's fixation index and Identity-by-State distance revealed that all individuals of Liangshan Semifine-wool, White Suffolk, and Butuo Black sheep were respectively clustered together, and the breeds could be separated from each other, whereas Jialuo and Mage sheep had the closest genetic relationship and could not be distinguished from each other. In conclusion, we provide a reference panel of genome-wide and high-quality SNPs in five sheep breeds in Sichuan, by which their genetic diversity and population structures were investigated.


Assuntos
Variação Genética/genética , Carneiro Doméstico/genética , Ovinos/genética , Animais , China , Cromossomos de Mamíferos/genética , Feminino , Frequência do Gene/genética , Heterozigoto , Masculino , Polimorfismo de Nucleotídeo Único/genética , Especificidade da Espécie
18.
Haemophilia ; 27(6): 1007-1021, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34494337

RESUMO

INTRODUCTION: Type 2N von Willebrand disease (VWD) is characterized by a decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII). Abnormal binding of FVIII to VWF (VWF:FVIIIB), results in low FVIII plasma levels, which can lead to a misdiagnosis of mild haemophilia A. Accurate diagnosis of type 2N VWD is essential for appropriate genetic counselling and therapy. This disease can be distinguished from haemophilia A by in vitro assays (measurement VWF:FVIIIB activity) and/or genetic analysis. AIM: To identify the current challenges in the diagnosis and treatment of this type of VWD and provide an in-depth description of the phenotypes and mutations identified. RESULTS: Twenty-eight patients had at least one type 2N mutation, and 13 of these had a type 2N mutation combined with other variations. Three type 2N mutations were detected: p.Arg816Trp, p.Arg854Gln, and p.Arg763Ser. Two of these are the most frequently described mutations worldwide. This mutational spectrum differs from the broad spectrum seen in neighbouring France, where at least eight distinct 2N mutations have been found. In the PCM-EVW-ES cohort, 11 asymptomatic type 2N carriers with borderline FVIII plasma levels would probably have been excluded if the evaluation had been based on clinical and laboratory data only. Likewise, three patients with a severe phenotype would have been classified as homozygous for a 2N mutation if only the phenotype study had been performed. CONCLUSION: The high detection yield and affordability of next-generation sequencing support the use of this technology as a first-line diagnostic tool in this setting.


Assuntos
Hemofilia A , Doença de von Willebrand Tipo 2 , Doenças de von Willebrand , Fator VIII/genética , Heterozigoto , Homozigoto , Humanos , Doença de von Willebrand Tipo 2/diagnóstico , Doença de von Willebrand Tipo 2/genética , Fator de von Willebrand/genética
19.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576214

RESUMO

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.


Assuntos
Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Sistema de Sinalização das MAP Quinases , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Animais , Doenças Autoimunes/terapia , Doença Crônica , Ativação Enzimática , Heterozigoto , Humanos , Inflamação/metabolismo , Leucemia/terapia , Erros Inatos do Metabolismo/metabolismo , Camundongos , Mutação , Polimorfismo Genético , Isoformas de Proteínas , Receptores de Glucocorticoides/deficiência , Transtornos Respiratórios/terapia , Transdução de Sinais , Dermatopatias/terapia , Resultado do Tratamento
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