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BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is a significant contributor to global morbidity and mortality. This study investigated disparities in age, sex and socio-economic status in CKD and updated global prevalence estimates through systematic review and meta-analysis. METHODS: Five databases were searched from 2014 to 2022, with 14 871 articles screened, 119 papers included and data analysed on 29 159 948 participants. Random effects meta-analyses were conducted to determine overall prevalence, prevalence of stages 3-5 and prevalence in males/females. Influences of age, sex and socio-economic status were assessed in subgroup analyses, and risk of bias assessment and meta-regressions were conducted to explore heterogeneity. RESULTS: Overall prevalence of CKD was 13.0% (11.3-14.8%) and 6.6% (5.6-7.8%) for stages 3-5. Prevalence was higher in studies of older populations (19.3% for stages 1-5, 15.0% for stages 3-5) and meta-regression demonstrated association of age, body mass index, diabetes and hypertension with prevalence of stages 3-5. The prevalence of CKD stages 1-5 was similar in males and females (13.1% versus 13.2%) but prevalence of stages 3-5 was higher in females (6.4% versus 7.5%). Overall prevalence was 11.4%, 15.0% and 10.8% in low, middle and high-income countries respectively; for stages 3-5 prevalence was 4.0%, 6.7% and 6.8%, respectively. Included studies were at moderate-high risk of bias in the majority of cases (92%), and heterogeneity was high. CONCLUSION: This study provides a comprehensive assessment of CKD prevalence, highlighting important disparities related to age, sex and socio-economic status. Future research should focus on targeted screening and treatment approaches, improving access to care and more effective data monitoring, particularly in low or middle income countries.
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Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.
Assuntos
Proteínas Contráteis/genética , Miopatias Distais/genética , Proteínas dos Microfilamentos/genética , Actinas/metabolismo , Adulto , Idoso , Austrália , Cromossomos Humanos Par 7/genética , Proteínas Contráteis/metabolismo , Miopatias Distais/metabolismo , Miopatias Distais/patologia , Feminino , Filaminas , Humanos , Itália , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Mutação , Linhagem , Estrutura Terciária de Proteína/genéticaRESUMO
We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies.
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Genes Dominantes , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Miopatias da Nemalina/genética , Idade de Início , Sequência de Aminoácidos , Animais , Criança , Cromossomos Humanos Par 15 , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
OBJECTIVE: To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center. METHODS: We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeqTM probe-based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high-coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician. RESULTS: Six hundred and sixty-five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E-9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes. INTERPRETATION: A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease-specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under-recognized pathogenic variants.
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Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Encaminhamento e Consulta , Adulto JovemAssuntos
Infecções Bacterianas/microbiologia , Bronquiectasia/microbiologia , Fibrose Cística/microbiologia , Adulto , Idoso , Antibacterianos/farmacologia , Infecções Bacterianas/diagnóstico , Bronquiectasia/diagnóstico , Fibrose Cística/diagnóstico , Humanos , Inflamação , Metagenoma , Pessoa de Meia-Idade , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/isolamento & purificação , RNA Ribossômico 16S/genética , Escarro/microbiologiaRESUMO
BACKGROUND: The lower airways harbor a community of bacterial species which is altered in asthma. OBJECTIVES: We examined whether the lower airway microbiota were related to measures of asthma severity. METHODS: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. RESULTS: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia. CONCLUSIONS: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.
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Asma/microbiologia , Microbiota , Fenótipo , Adulto , Asma/fisiopatologia , Contagem de Células , Feminino , Humanos , Pulmão/microbiologia , Pulmão/fisiopatologia , Masculino , Microbiota/genética , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Escarro/microbiologiaRESUMO
Leigh syndrome (LS) is a progressive mitochondrial neurodegenerative disorder, whose symptoms most commonly include psychomotor delay with regression, lactic acidosis and a failure to thrive. Here we describe three siblings with LS, but with additional manifestations including hypertrophic cardiomyopathy, hepatosplenomegaly, cholestatic hepatitis, and seizures. All three affected siblings were found to be homoplasmic for an m. 5559A>G mutation in the T stem of the mitochondrial DNA-encoded MT-TW by next generation sequencing. The m.5559A>G mutation causes a reduction in the steady state levels of tRNA(Trp) and this decrease likely affects the stability of other mitochondrial RNAs in the patient fibroblasts. We observe accumulation of an unprocessed transcript containing tRNA(Trp), decreased de novo protein synthesis and consequently lowered steady state levels of mitochondrial DNA-encoded proteins that compromise mitochondrial respiration. Our results show that the m.5559A>G mutation at homoplasmic levels causes LS in association with severe multi-organ disease (LS-plus) as a consequence of dysfunctional mitochondrial RNA metabolism.
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Doença de Leigh/genética , Doença de Leigh/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Processamento Pós-Transcricional do RNA , RNA de Transferência de Triptofano/genética , RNA de Transferência de Triptofano/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação Puntual , IrmãosRESUMO
BACKGROUND: Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. METHODS: Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. RESULTS: PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. CONCLUSION: In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.
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Acidose Láctica/genética , Anemia Sideroblástica/genética , Miopatias Mitocondriais/genética , Tirosina-tRNA Ligase/genética , Acidose Láctica/metabolismo , Adolescente , Adulto , Anemia Sideroblástica/metabolismo , Criança , Pré-Escolar , DNA Mitocondrial/genética , Feminino , Humanos , Hidroliases/genética , Hidroliases/metabolismo , Lactente , Recém-Nascido , Miopatias Mitocondriais/metabolismo , Tirosina-tRNA Ligase/metabolismo , Adulto JovemRESUMO
The clinically and genetically heterogenous foetal akinesias have low rates of genetic diagnosis. Exome sequencing of two siblings with phenotypic lethal multiple pterygium syndrome identified compound heterozygozity for a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) in glycogen branching enzyme 1 (GBE1). GBE1 mutations cause glycogen storage disease IV (GSD IV), including a severe foetal akinesia sub-phenotype. Re-investigating the muscle pathology identified storage material, consistent with GSD IV, which was confirmed biochemically. This study highlights the power of exome sequencing in genetically heterogeneous diseases and adds multiple pterygium syndrome to the phenotypic spectrum of GBE1 mutation.
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Anormalidades Múltiplas/genética , Artrogripose/genética , Exoma/genética , Genótipo , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio/genética , Hipertermia Maligna/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Anormalidades da Pele/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Aminoácidos , Artrogripose/diagnóstico , Austrália , Biópsia , Evolução Fatal , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Humanos , Recém-Nascido , Masculino , Hipertermia Maligna/diagnóstico , Dados de Sequência Molecular , Músculo Esquelético/patologia , Linhagem , Anormalidades da Pele/diagnósticoRESUMO
Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected-unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPT(per)) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPT(per) which represents 690 independent families. Suggestive linkage (LOD > or = 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPT(per)), and 2.25 (IgE) near markers D1S1653, D3S2322-D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPT(per)) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders.
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Ligação Genética , Predisposição Genética para Doença , Genoma Humano , Hipersensibilidade Imediata/genética , População Branca , Adolescente , Adulto , Animais , Asma/genética , Criança , Pré-Escolar , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes CutâneosRESUMO
We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.