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1.
Equine Vet J ; 52(1): 34-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30903710

RESUMO

BACKGROUND: Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocular SCC in the Haflinger breed. A sample of Belgian horses with unknown SCC phenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate that chestnut coat colour may predispose to the development of SCC. OBJECTIVES: To determine if DDB2 c.1013C>T is a risk factor for ocular SCC in a strictly phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocular SCC. STUDY DESIGN: Retrospective and prospective case identification, genetic investigation. METHODS: Genomic DNA was isolated from blood, hair or formalin-fixed paraffin-embedded tissue from 25 Belgian horses with histologically confirmed ocular SCC and 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping for DDB2 c.1013C>T and coat colour alleles were performed. Exons of DDB2 were sequenced in four cases and two controls. Associations were analysed by Chi-square or Fisher's exact tests and relative risk was calculated. RESULTS: Homozygosity for DDB2 c.1013C>T was significantly associated with ocular SCC (P = 7.4 × 10-7 ). Seventy-six per cent of affected horses were homozygous for the variant. Relative risk for homozygous horses developing SCC was 4.0 (P = 1.0 × 10-4 ). Sequencing DDB2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. MAIN LIMITATIONS: Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with this MC1R variant could not be investigated. CONCLUSIONS: A missense variant, DDB2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available.


Assuntos
Carcinoma de Células Escamosas/veterinária , Proteínas de Ligação a DNA/genética , Neoplasias Oculares/veterinária , Predisposição Genética para Doença , Doenças dos Cavalos/genética , Mutação de Sentido Incorreto , Animais , Cavalos
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1107-1110, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703137

RESUMO

OBJECTIVE: To explore the genetic basis for a pedigree affected with Marfan syndrome (MFS). METHODS: Clinical data of the patients was collected. With genomic DNA extracted from peripheral blood samples, potential mutation was detected by targeted exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis. RESULTS: Targeted exome sequencing and Sanger sequencing revealed a missense c.649T to C(p.Trp217Arg) variant in the exon 7 of FBN1 gene, which was unreported previously. Bioinformatics analysis suggested that the variant can cause amino acid replacement and affect the structure and function of fibrillin-1. CONCLUSION: A novel missense variant of the FBN1 gene was identified, which probably underlies the autosomal dominant MFS in this pedigree.


Assuntos
Fibrilina-1/genética , Síndrome de Marfan/genética , Mutação de Sentido Incorreto , Análise Mutacional de DNA , Éxons , Fibrilinas , Humanos , Mutação , Linhagem
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 957-960, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598935

RESUMO

OBJECTIVE: To explore the genetic basis of a patient with early-onset Parkinson disease from a consanguineous family. METHODS: Homozygosity mapping and Sanger sequencing of cDNA were used to identify the causative mutation. RESULTS: A homozygous missense variation (c.56C>G, p.Thr19Arg) in the PARK7 gene was identified in the patient. In silico analysis suggested the c.56C>G variation to be pathogenic. CONCLUSION: Homozygous c.56C>G variation of the PARK7 gene was the disease-causing variation in this family.


Assuntos
Doença de Parkinson/genética , Proteína Desglicase DJ-1/genética , Consanguinidade , Homozigoto , Humanos , Mutação de Sentido Incorreto , Linhagem
4.
Medicine (Baltimore) ; 98(41): e17566, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593141

RESUMO

RATIONALE: Coexistence of Fabry disease and IgM nephropathy is rare. The varying severity and unapparent clinical manifestation of Fabry disease makes it difficult to recognize when coexisting with another more prevalent cause of nephropathy requiring electron microscopy and genetic testing to confirm their coexistence. PATIENT CONCERNS: A 54-year-old female presented with proteinuria without any clinical signs or family history of Fabry disease. DIAGNOSES: Immunostaining of the renal biopsy identified mesangial IgM deposition diagnosing it as IgM nephropathy. The light microscopy indicated prominent vacuolization of podocytes. Further examination of toluidine blue stained semi-thin sections and electron microscopy revealed blue bodies and myelin bodies in the cytoplasm of podocytes, respectively. Mutation analysis detected missense mutation establishing the diagnosis of coexisting Fabry disease. INTERVENTIONS: The patient was treated with angiotensin-converting enzyme inhibitors. Enzyme replacement therapy was not administered due to financial constraints. OUTCOMES: After 2 months of treatment the patient demonstrated urine protein to creatinine ratio of 0.21 g/g. LESSONS: Identifying coexistence of Fabry disease with other nephropathy requires meticulous pathologic investigations including electron microscopy especially when Fabry disease presents with atypical phenotype.


Assuntos
Doença de Fabry/complicações , Glomerulonefrite/diagnóstico , Imunoglobulina M/imunologia , Podócitos/ultraestrutura , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Terapia de Reposição de Enzimas/economia , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/patologia , Feminino , Glomerulonefrite/complicações , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Humanos , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Podócitos/patologia , Proteinúria/diagnóstico , Proteinúria/etiologia , Resultado do Tratamento
5.
Cell Mol Life Sci ; 76(21): 4221-4232, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584127

RESUMO

In the past two decades, transmembrane channel-like (TMC) proteins have attracted a significant amount of research interest, because mutations of Tmc1 lead to hereditary deafness. As evolutionarily conserved membrane proteins, TMC proteins are widely involved in diverse sensorimotor functions of many species, such as hearing, chemosensation, egg laying, and food texture detection. Interestingly, recent structural and physiological studies suggest that TMC channels may share a similar membrane topology with the Ca2+-activated Cl- channel TMEM16 and the mechanically activated OSCA1.2/TMEM63 channel. Namely, these channels form dimers and each subunit consists of ten transmembrane segments. Despite this important structural insight, a key question remains: what is the gating mechanism of TMC channels? The major technical hurdle to answer this question is that the reconstitution of TMC proteins as functional ion channels has been challenging in mammalian heterologous systems. Since TMC channels are conserved across taxa, genetic studies of TMC channels in model organisms such as C. elegans, Drosophila, and zebrafish may provide us critical information on the physiological function and regulation of TMCs. Here, we present a comparative overview on the diverse functions of TMC channels in different species.


Assuntos
Canais Iônicos/metabolismo , Animais , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Canais Iônicos/química , Canais Iônicos/genética , Mecanotransdução Celular , Mutação de Sentido Incorreto , Neurônios/metabolismo , Propriocepção , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
6.
BMC Med Genet ; 20(1): 150, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477031

RESUMO

BACKGROUND: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. METHODS: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. RESULTS: Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). CONCLUSIONS: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação , Receptor ErbB-2/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Bangladesh/etnologia , Sequência de Bases , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Feminino , Mutação da Fase de Leitura , Testes Genéticos , Variação Genética , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNA
7.
Shanghai Kou Qiang Yi Xue ; 28(3): 268-274, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489414

RESUMO

PURPOSE: To identify the potentially pathogenic mutations in patients with ectodermal dysplasia (ED) and to investigate the pathogenicity of mutations by functional studies. METHODS: Eight Chinese ED patients were included in this study. Peripheral venous blood was taken from the patients and DNA was extracted. Whole-exome sequencing (WES) was performed using DNA samples. After quality control of the sequencing data, the potentially pathogenic mutations were screened. The pathogenicity of the mutations was predicted in silico. Immunofluorescence study and dual luciferase assays were performed to investigate the pathogenicity of the mutations. RESULTS: The effective rates of all sequencing samples were above 97.5% and the error rates were less than 0.03%. The proportions of Q20 were more than 97.0%. The average sequencing depths of the target region were more than 90×. The sequencing data were acceptable for further analysis. After data screening, three missense mutations of EDA were detected, including c.959A>G, c.1073A>G and c.1001G>A. The allele frequency was low in population database for all three mutations and in silico analysis indicated all three mutations were disease-causing. Immunofluorescence analysis showed that p65 protein nuclear translocation was compromised by EDA mutations, dual luciferase assays also showed that the activation of NF-κB pathway was decreased by EDA mutations. CONCLUSIONS: This study identified EDA mutations in Chinese ED patients and further verified the pathogenicity of the mutations by functional studies, contributing to the understanding of the pathogenesis of ED.


Assuntos
Displasia Ectodérmica , Mutação de Sentido Incorreto , Grupo com Ancestrais do Continente Asiático , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Humanos , Mutação , NF-kappa B
8.
Eur J Endocrinol ; 181(5): K43-K53, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539878

RESUMO

Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. Results: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.


Assuntos
Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento Insulin-Like I/deficiência , Mutação de Sentido Incorreto/genética , Anormalidades Múltiplas/genética , Proliferação de Células , Biologia Computacional , Simulação por Computador , Retardo do Crescimento Fetal/genética , Células HEK293 , Homozigoto , Humanos , Lactente , Fator de Crescimento Insulin-Like I/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatomedina/genética , Tirosina/genética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 757-760, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400121

RESUMO

OBJECTIVE: To identify pathogenic variations of EXT1 and EXT2 genes in two Chinese pedigrees affected with hereditary multiple exostosis (HME). METHODS: Genomic DNA was extracted from peripheral blood samples using a phenol-chloroform method. PCR and Sanger sequencing was conducted to amplify the exons and the flanking intronic regions of the EXT1 and EXT2 genes. RESULTS: DNA sequencing has revealed a heterozygous missense variation c.812A>G (p.Tyr271Cys) in the exon 1 of EXT1 in pedigree 1, and a heterozygous frameshift variation c.1431dup (p.Ser478Leufs*43) in the exon 6 of EXT1 in the proband from pedigree 2. Both variations have co-segregated with the disease phenotype, which was also consistent with previous report. CONCLUSION: Two heterozygous pathogenic variations underlying HME have been identified. The result has facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Análise Mutacional de DNA , Exostose Múltipla Hereditária/patologia , Mutação da Fase de Leitura , Humanos , Mutação de Sentido Incorreto , Linhagem
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 794-797, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400130

RESUMO

OBJECTIVE: To explore the molecular basis for a pedigree affected with Darier-White disease. METHODS: Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools. RESULTS: A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein. CONCLUSION: The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).


Assuntos
Doença de Darier/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Heterozigoto , Humanos , Mutação de Sentido Incorreto , Linhagem
11.
BMC Med Genet ; 20(1): 133, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370824

RESUMO

BACKGROUND: Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet. METHODS: We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics. RESULTS: Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM_005450) c.124C > T, p.(Pro42Ser) in all patients. This c.124C > T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic. CONCLUSION: Our results suggest that heterozygous c.124C > T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte/genética , Articulações dos Dedos/anormalidades , Predisposição Genética para Doença/genética , Artropatias/congênito , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Sequência de Bases , Éxons , Articulações dos Dedos/diagnóstico por imagem , Articulações dos Dedos/fisiopatologia , Pé/diagnóstico por imagem , Mãos/diagnóstico por imagem , Perda Auditiva/genética , Heterozigoto , Humanos , Artropatias/diagnóstico por imagem , Artropatias/genética , Artropatias/fisiopatologia , Modelos Moleculares , Linhagem , Fenótipo , Análise de Sequência de DNA , Análise de Sequência de Proteína , Sequenciamento Completo do Exoma
12.
Gene ; 715: 144027, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31374327

RESUMO

OBJECTIVES: To explore the clinical and molecular characteristics of a Chinese Zhuang minority patient with leukocyte adhesion deficiency type-1 (LAD-1) and glucose-6-phosphate dehydrogenase deficiency (G6PDD). METHODS: Routine clinical and physical examinations were performed, and patient data was collected and analyzed. Protein expression levels of Itgb2 and glucose-6-phosphate dehydrogenase (G6pd) proteins were assessed by flow cytometry and the glucose-6-phosphate (G6P) substrate method, respectively. Whole exome sequencing was performed to investigate genetic variations of the patient and his parents. RESULTS: The patient had fester disease and delayed separation of the umbilical cord at birth. Staphylococcus was detected in the fluid secretion of the auditory meatus of the patient. He exhibited a recurrent cheek scab, swollen hand, and swollen gum. Hematological examination indicated dramatic elevation of leukocytes including lymphocytes, monocytes, neutrophils and eosinophils. A novel homozygous mutation was detected in the ITGB2 gene of the patient, which was determined to be a two nucleotide deletion at the site of c.1537-1538 (c.1537-1538delGT), causing a frameshift of 24 amino acids from p.513 and inducing a stop codon (p.V513Lfs*24). A base substitution mutation was identified at c.1466 (c.1466G>T) of G6PD on chromosome X of the patient, which resulted in an amino acid change from arginine to leucine at p.489 (p.R489L). The patient also showed deficient lymphocyte expression of CD18 (2.99%) and significant downregulation of the G6pd protein. CONCLUSIONS: The patient was diagnosed with G6PDD and moderate LAD-1. The combination of LAD-1 and G6PDD in this case may have been due to the high incidence of genetic disease in this minority ethnic population. Analyzing existing LAD-1 and G6PDD cases from different populations can facilitate disease diagnosis and treatment. Particularly, reporting pathogenic mutations of LAD-1 and G6PDD will be crucial for genetic testing and prenatal diagnosis in an effort to decrease the incidence of these diseases.


Assuntos
Antígenos CD18/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Homozigoto , Síndrome da Aderência Leucocítica Deficitária/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Antígenos CD18/metabolismo , Deficiência de Glucosefosfato Desidrogenase/patologia , Humanos , Lactente , Síndrome da Aderência Leucocítica Deficitária/metabolismo , Síndrome da Aderência Leucocítica Deficitária/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino
13.
Hematol Oncol ; 37(4): 434-437, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465530

RESUMO

The conventional thrombotic risk stratification in essential thrombocythemia (ET) distinguishes patients in two risk groups based on previous thrombosis and age (< or >60). The IPSET-thrombosis takes into account four risk factors: age greater than 60 years and the presence of CV risk factors, thrombosis history and JAK2 V617F presence. The revised IPSET-thrombosis uses three adverse variables to delineate four risk categories: age greater than 60, thrombosis history, and JAK2 V617F presence. We compared different risk models in the estimation of thrombotic risk in 191 patients with ET and the role of specific driver mutations affecting overall survival, according to thrombotic risk. We also evaluated the mutational status of patients showing history of thrombosis or cardiovascular events versus patients who did not. Finally, we verified whether the thrombotic risk had a significant impact on survival in our ET patients. The data analysis has been performed through the conventional statistics and overall survival estimated by using the Kaplan-Meyer method. Interestingly, either using the traditional system for thrombotic risk or the IPSET-t prognostic score or the current stratification for the thrombotic risk, high-risk patients are always highly represented. This evidence is of note, being the high-risk category indicated for cytoreduction, affecting quality of life, despite the good overall prognosis of patients with ET diagnosis in general. The analysis of overall survival in our patients, according to different models for thrombotic risk, highlighted the poor prognosis of high-risk patients compared with those with a lower thrombotic risk, in particular when using traditional stratification and current stratification. In conclusion, the occurrence of thrombotic or cardiovascular events represents one of the most severe complications at diagnosis or during follow-up of ET despite current recommendations, having a significant impact on morbidity and survival.


Assuntos
Índice de Gravidade de Doença , Trombocitemia Essencial/complicações , Trombofilia/etiologia , Trombose/etiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Calreticulina/genética , Feminino , Seguimentos , Humanos , Incidência , Janus Quinase 2/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação de Sentido Incorreto , Prognóstico , Receptores de Trombopoetina/genética , Recidiva , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Trombocitemia Essencial/genética , Trombocitemia Essencial/mortalidade , Trombofilia/genética , Trombose/epidemiologia , Adulto Jovem
14.
BMC Neurol ; 19(1): 198, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31421687

RESUMO

BACKGROUND: Myofibrillar myopathies (MFMs) are a genetically heterogeneous group of muscle disorders. Mutations in the filamin C gene (FLNC) have previously been identified in patients with MFM. The phenotypes of FLNC-related MFM are heterogeneous. CASE PRESENTATION: The patient was a 37-year-old male who first experienced weakness in the distal muscles of his hand, which eventually spread to the lower limbs and proximal muscles. Serum creatine kinase levels were moderately elevated. Obvious neuropathic changes in the electromyographic exam and edema changes in lower distal limb magnetic resonance imaging were observed. Histopathological examination revealed the presence of abnormal protein aggregates and angular atrophy in some muscle fibers. Ultrastructural analysis showed inordinate myofibrillar structures and dissolved myofilaments. DNA sequencing analysis detected a heterozygous missense mutation (c.7123G > A, p.V2375I) in the immunoglobulin (Ig)-like domain 21 of FLNC. CONCLUSIONS: FLNC mutation c.7123G > A, p.V2375I in the immunoglobulin (Ig)-like domain 21 can be associated with distal myopathy with typical MFM features and lower motor neuron syndrome. Although electromyographic examination of our patient showed obvious neuropathic changes, MFM could not be excluded. Therefore, genetic testing is necessary to make an accurate diagnosis.


Assuntos
Doença dos Neurônios Motores/genética , Distrofias Musculares/genética , Adulto , Heterozigoto , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Fenótipo , Síndrome
15.
Gene ; 718: 144072, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31446095

RESUMO

Disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal and sex is atypical. It is difficult to diagnose and manage patients with DSD in clinical practice, and the molecular etiology of DSD is still not completely understood. Here, we identified two novel pathogenic mutations from three unrelated Chinese patients with 46,XY complete gonadal dysgenesis (CGD) that is a clinical subgroup of DSD by whole exome sequencing. A novel mutation in the SRY gene (c.161delG) was identified in the first patient, and the second patient carried a novel missense mutation in the MAP3K1 gene (c.2117T>G). Bioinformatics analysis found that the deletion of SRY (c.161delG) led to a premature stop codon at amino acid 59 in the SRY protein, which resulted in lacking the DNA binding domain of SRY protein. Functional studies found that the missense mutation in the MAP3K1 gene (c.2117T>G) could interfere with the gene function through increasing the phosphorylation of the downstream targets of MAP3K1, ERK1/2 and p38, which resulted in reducing testis-determining factor SOX9 expression and increasing ovary-promoting factor ß-catenin activity. According to the American college of medical genetics and genomics (ACMG) standards and guidelines, these mutations were categorized as "pathogenic" mutations. Thus, our findings provide two novel pathogenic mutations associated with 46,XY CGD that can improve the etiological diagnosis for 46,XY CGD. ABBREVIATIONS.


Assuntos
Sequência de Bases , Disgenesia Gonadal 46 XY , MAP Quinase Quinase Quinase 1 , Mutação de Sentido Incorreto , Deleção de Sequência , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/metabolismo , Disgenesia Gonadal 46 XY/patologia , Humanos , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteína da Região Y Determinante do Sexo/genética , Proteína da Região Y Determinante do Sexo/metabolismo
16.
17.
Anim Genet ; 50(5): 546-549, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365140

RESUMO

The Ehlers-Danlos syndromes (EDSs) are a heterogeneous group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and tissue fragility. Inherited disorders similar to human EDS have been reported in different mammalian species. In the present study, we investigated a female mixed-breed dog with clinical signs of EDS. Whole-genome sequencing of the affected dog revealed two missense variants in the TNXB gene, encoding the extracellular matrix protein tenascin XB. In humans, TNXB genetic variants cause classical-like EDS or the milder hypermobile EDS. The affected dog was heterozygous at both identified variants. Each variant allele was transmitted from one of the case's parents, consistent with compound heterozygosity. Although one of the variant alleles, XM_003431680.3:c.2012G>A, p.(Ser671Asn), was private to the family of the affected dog and absent from whole-genome sequencing data of 599 control dogs, the second variant allele, XM_003431680.3:c.2900G>A, p.(Gly967Asp), is present at a low frequency in the Chihuahua and Poodle population. Given that TNXB is a functional candidate gene for EDS, we suggest that compound heterozygosity for the identified TNXB variants may have caused the EDS-like phenotype in the affected dog. Chihuahuas and Poodles should be monitored for EDS cases, which might confirm the hypothesized pathogenic effect of the segregating TNXB variant.


Assuntos
Doenças do Cão/genética , Síndrome de Ehlers-Danlos/genética , Mutação de Sentido Incorreto , Tenascina/genética , Animais , Cães , Feminino , Heterozigoto
18.
Cancer Sci ; 110(10): 3340-3349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342590

RESUMO

Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion-metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain. MET-knockout cells were prepared and reconstituted with WT-MET or V370D-MET. HGF stimulation induced MET dimerization and biological responses in cells reconstituted with WT-MET, but HGF did not induce MET dimerization and failed to induce biological responses in V370D-MET cells. The V370D mutation abrogated HGF-dependent drug resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). Compared with WT-MET cells, V370D-MET cells showed different activation patterns in receptor tyrosine kinases upon exposure to survival/growth-stressed conditions. Surface plasmon resonance analysis indicated that affinity between the extracellular region of V370D-MET and HGF was reduced compared with that for WT-MET. Further analysis of the association between V370D-MET and the separate domains of HGF indicated that the SP domain of HGF was unchanged, but its association with the NK4 domain of HGF was mostly lost in V370D-MET. These results indicate that the V370D mutation in the MET receptor impairs the functional association with HGF and is therefore a loss-of-function mutation. This mutation may change the dependence of cancer cell growth/survival on signaling molecules, which may promote cancer cell characteristics under certain conditions.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/genética , Animais , Células CHO , Linhagem Celular Tumoral , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Técnicas de Inativação de Genes , Humanos , Mutação com Perda de Função , Domínios Proteicos , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Proteínas Proto-Oncogênicas c-met/metabolismo , Ativação Transcricional
19.
Clin Biochem ; 73: 50-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344365

RESUMO

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. METHODS: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. RESULTS: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40-82%). An additive effect on the reduction of enzymatic activity (1-17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. CONCLUSIONS: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Alelos , Modelos Moleculares , Mutação de Sentido Incorreto , Esteroide 21-Hidroxilase , Adolescente , Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Adulto , Substituição de Aminoácidos , Animais , Células COS , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Domínios Proteicos , Esteroide 21-Hidroxilase/química , Esteroide 21-Hidroxilase/genética
20.
Gene ; 715: 143970, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31330235

RESUMO

BACKGROUND: Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3'UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. CONCLUSIONS: Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas , Mutação de Sentido Incorreto , Penetrância , Receptor Notch1/genética , Adulto , Alelos , Substituição de Aminoácidos , Éxons , Feminino , Heterozigoto , Homozigoto , Humanos , Íntrons , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sequência de DNA
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