RESUMO
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
Assuntos
Complexo 1 de Proteínas Adaptadoras/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Alelos , Animais , Análise Mutacional de DNA , Feminino , Células HEK293 , Humanos , Masculino , Linhagem , Ratos , Peixe-Zebra/genéticaRESUMO
Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.
Assuntos
Alelos , Genes Recessivos , Deficiência Intelectual/genética , Metiltransferases/genética , Microcefalia/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , LinhagemRESUMO
Renewable energy resources have gained considerable attention in recent years due to their efficiency and economic benefits. Their proportion of total energy use continues to grow over time. Photovoltaic (PV) cell and wind energy generation are the least-expensive new energy sources in most countries. Renewable energy technologies significantly contribute to climate mitigation and provide economic benefits. Apart from these advantages, renewable energy sources, particularly solar energy, have drawbacks, for instance restricted energy supply, reliance on weather conditions, and being affected by several kinds of faults, which cause a high power loss. Usually, the local PV plants are small in size, and it is easy to trace any fault and defect; however, there are many PV cells in the grid-connected PV system where it is difficult to find a fault. Keeping in view the aforedescribed facts, this paper presents an intelligent model to detect faults in the PV panels. The proposed model utilizes the Convolutional Neural Network (CNN), which is trained on historic data. The dataset was preprocessed before being fed to the CNN. The dataset contained different parameters, such as current, voltage, temperature, and irradiance, for five different classes. The simulation results showed that the proposed CNN model achieved a training accuracy of 97.64% and a testing accuracy of 95.20%, which are much better than the previous research performed on this dataset.
Assuntos
Fontes de Energia Elétrica , Modelos Teóricos , Algoritmos , Vento , Aprendizado de MáquinaRESUMO
Automatic License Plate Detection (ALPD) is an integral component of using computer vision approaches in Intelligent Transportation Systems (ITS). An accurate detection of vehicles' license plates in images is a critical step that has a substantial impact on any ALPD system's recognition rate. In this paper, we develop an efficient license plate detecting technique through the intelligent combination of Faster R-CNN along with digital image processing techniques. The proposed algorithm initially detects vehicle(s) in the input image through Faster R-CNN. Later, the located vehicle is analyzed by a robust License Plate Localization Module (LPLM). The LPLM module primarily uses color segmentation and processes the HSV image to detect the license plate in the input image. Moreover, the LPLM module employs morphological filtering and dimension analysis to find the license plate. Detailed trials on challenging PKU datasets demonstrate that the proposed method outperforms few recently developed methods by producing high license plates detection accuracy in much less execution time. The proposed work demonstrates a great feasibility for security and target detection applications.
Assuntos
Algoritmos , Processamento de Imagem Assistida por Computador , Inteligência , Projetos de PesquisaRESUMO
The proposed work uses fixed lag smoothing on the interactive multiple model-integrated probabilistic data association algorithm (IMM-IPDA) to enhance its performance. This approach makes use of the advantages of the fixed lag smoothing algorithm to track the motion of a maneuvering target while it is surrounded by clutter. The suggested method provides a new mathematical foundation in terms of smoothing for mode probabilities in addition to the target trajectory state and target existence state by including the smoothing advantages. The suggested fixed lag smoothing IMM-IPDA (FLs IMM-IPDA) method's root mean square error (RMSE), true track rate (TTR), and mode probabilities are compared to those of other recent algorithms in the literature in this study. The results clearly show that the proposed algorithm outperformed the already-known methods in the literature in terms of these above parameters of interest.
Assuntos
Algoritmos , Movimento (Física) , ProbabilidadeRESUMO
Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.
Assuntos
Catarata/genética , Mutação de Sentido Incorreto , Sinais de Orientação para Peroxissomos , Receptor 1 de Sinal de Orientação para Peroxissomos/genética , Peroxissomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico Ativo , Catarata/congênito , Catarata/metabolismo , Cromossomos Humanos Par 12 , Consanguinidade , Feminino , Ligação Genética , Humanos , Cristalino/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor 1 de Sinal de Orientação para Peroxissomos/metabolismo , Proteína Sequestossoma-1/metabolismo , Sequenciamento do ExomaRESUMO
We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
Assuntos
Agressão/fisiologia , Nanismo/genética , Variação Genética/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Adolescente , Animais , Criança , Drosophila melanogaster/genética , Éxons/genética , Feminino , Técnicas de Inativação de Genes/métodos , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA de Transferência/genéticaRESUMO
PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem , Sequenciamento do ExomaRESUMO
COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.
Assuntos
Surdez/genética , Proteínas da Matriz Extracelular/genética , Genes Recessivos/genética , Mutação com Perda de Função/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cóclea/metabolismo , Cóclea/patologia , Códon sem Sentido/genética , Surdez/patologia , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , LinhagemRESUMO
Purpose: This study was designed to identify the pathogenic variants in three consanguineous families with congenital cataracts segregating as a recessive trait. Methods: Consanguineous families with multiple individuals manifesting congenital cataracts were ascertained. All participating members underwent an ophthalmic examination. A small aliquot of the blood sample was collected from all participating individuals, and genomic DNAs were extracted. Homozygosity-based linkage analysis was performed using short tandem repeat (STR) markers. The haplotypes were constructed with alleles of the STR markers, and the two-point logarithm of odds (LOD) scores were calculated. The candidate gene was sequenced bidirectionally to identify the disease-causing mutations. Results: Linkage analysis localized the disease interval to chromosome 3p in three families. Subsequently, bidirectional Sanger sequencing identified two novel mutations-a single base deletion resulting in a frameshift (c.3196delC; p.His1066IlefsTer10) mutation and a single base substitution resulting in a nonsense (c.4270C>T; p.Arg1424Ter) mutation-and a known missense (c.4127T>C, p.Leu1376Pro) mutation in FYCO1. All three mutations showed complete segregation with the disease phenotype and were absent in 96 ethnically matched control individuals. Conclusions: We report two novel mutations and a previously reported mutation in FYCO1 in three large consanguineous families. Taken together, mutations in FYCO1 contribute nearly 15% to the total genetic load of autosomal recessive congenital cataracts in this cohort.
Assuntos
Catarata/genética , Proteínas Associadas aos Microtúbulos/genética , Adulto , Alelos , Catarata/sangue , Catarata/congênito , Catarata/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 3/genética , Códon sem Sentido , Consanguinidade , Família , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Ligação Genética , Predisposição Genética para Doença , Haplótipos , Homozigoto , Humanos , Lactente , Masculino , Repetições de Microssatélites , Proteínas Associadas aos Microtúbulos/sangue , Mutação de Sentido Incorreto , Paquistão , Linhagem , FilogeniaRESUMO
Waste management is an emerging focus in Pakistan. Specifically, waste-to-energy (WtE) projects are conceived to obtain benefits from municipal waste collection in metropolitan cities. This study provides a brief background of WtE potential, waste collection statistics, type of generated wastes, and current measures to build the confidence of investors in WtE projects. In addition, a brief overview of government efforts for WtE and delineation of licensing requirements for power generation are discussed. The parameters laid down for the determination of tariffs for municipal waste management power projects and the cost accounted for each parameter are analyzed in detail. Similarly, this study deliberates on observations among stakeholders and compares Pakistan tariffs with those of neighboring countries.
Assuntos
Eliminação de Resíduos , Gerenciamento de Resíduos , Cidades , Paquistão , Resíduos Sólidos/análiseRESUMO
Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.
Assuntos
Segregação de Cromossomos/genética , Consanguinidade , Perda Auditiva/genética , Família , Feminino , Genes Recessivos , Predisposição Genética para Doença , Humanos , Masculino , Mutação/genética , Paquistão , LinhagemRESUMO
Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.
Assuntos
Aspartato-tRNA Ligase/genética , Doença de Leigh/genética , Aminoacil-RNA de Transferência/genética , Adulto , Sequência de Aminoácidos/genética , Animais , Aspartato-tRNA Ligase/biossíntese , Surdez/genética , Surdez/patologia , Orelha Interna/metabolismo , Orelha Interna/patologia , Feminino , Fibroblastos , Expressão Gênica/genética , Predisposição Genética para Doença , Humanos , Doença de Leigh/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação de Sentido Incorreto/genética , Consumo de Oxigênio/genética , LinhagemRESUMO
CIB2 and GJB2 genes variants contribute significantly in familial cases of prelingual recessive hearing loss (HL). This study was aimed to determine the CIB2 and GJB2 variants and associated phenotype in 150 non-familial individuals with HL. After getting informed consent, 150 non-familial deaf patients were enrolled and blood samples were obtained for DNA extraction. Pure tone air conduction audiometry was performed. Coding exons of CIB2 and GJB2 genes were Sanger sequenced. A tetra primer ARMS assay was developed for recurrent CIB2 variant. Four bi-allelic GJB2 variants, c.71G>A p.(Trp24*), c.231G>A p.(Trp77*), c.235delC p.(Leu79Cysfs3*) and c.35delG p.(Gly11Leufs24*), were found in nine hearing impaired individuals. We also found four homozygotes and five carriers of c.380G>A p. (Arg127His) variant of controversial clinical significance. CIB2 sequencing revealed single recurrent variant c.272T>C p. (Phe91Ser) segregating with HL in ten individuals. Among our patients, c.71G>A (p.Trp24*) was the most common variant, accounted for 45% of GJB2 variants. Two known GJB2 variants, c.235delC p. (Leu79Cysfs3*) and c.310del14 p. (Lys105Argfs2*), are reported here for the first time in Pakistani population. Our data further support the benign nature of c.380G>A p. (Arg127His) variant. For CIB2, c.272T>C p. (Phe91Ser) is the second common cause of HL among our sporadic cases. Phenotypically, in our patients, individuals homozygous for GJB2 variants had profound HL, whereas CIB2 homozygotes had severe to profound prelingual HL. Our results suggest that GJB2 and CIB2 are common cause of HL in different Pakistani ethnicities.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Conexinas/genética , Surdez/genética , Doenças Genéticas Inatas/genética , Testes Genéticos , Mutação , Fenótipo , Conexina 26 , Surdez/etnologia , Feminino , Aconselhamento Genético , Humanos , Masculino , Paquistão/etnologiaRESUMO
Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.
Assuntos
Surdez/genética , Surdez/patologia , Mutação , Miosinas/genética , Miosinas/metabolismo , Processamento Alternativo , Animais , Surdez/metabolismo , Modelos Animais de Doenças , Orelha Interna/crescimento & desenvolvimento , Orelha Interna/metabolismo , Orelha Interna/patologia , Éxons , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Estereocílios/metabolismo , Estereocílios/patologiaRESUMO
Pathogenic mutations of MARVELD2, encoding tricellulin, a tricelluar tight junction protein, cause autosomal recessive non-syndromic hearing loss (DFNB49) in families of Pakistan and Czech Roma origin. In fact, they are a significant cause of prelingual hearing loss in the Czech Roma, second only to GJB2 variants. Previously, we reported that mice homozygous for p.Arg497* variant of Marveld2 had a broad phenotypic spectrum, where defects were observed in the inner ear, heart, mandibular salivary gland, thyroid gland and olfactory epithelium. The current study describes the types and frequencies of MARVELD2 alleles and clinically reexamines members of DFNB49 families. We found that MARVELD2 variants are responsible for about 1.5 % (95 % CI 0.8-2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. In addition, we identified a novel large deletion in a single family, which appears to have resulted from non-allelic homologous recombination between two similar Alu short interspersed elements. Finally, we observed no other clinical manifestations co-segregating with hearing loss in DFNB49 human families, and hypothesize that the additional abnormalities in the Marveld2 mutant mouse indicates a critical non-redundant function for tricellulin in other organ systems.
Assuntos
Perda Auditiva Neurossensorial/genética , Proteína 2 com Domínio MARVEL/genética , Adolescente , Animais , Células Cultivadas , Criança , Conexina 26 , Conexinas , Análise Mutacional de DNA , Cães , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Paquistão , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , EslováquiaRESUMO
Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.
Assuntos
Epilepsia , Deficiência Intelectual , Espasticidade Muscular , Mutação de Sentido Incorreto , Linhagem , Ubiquitina-Proteína Ligases , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Ubiquitina-Proteína Ligases/genética , Masculino , Feminino , Epilepsia/genética , Paquistão , Espasticidade Muscular/genética , Transtornos Psicomotores/genética , Transtornos Psicomotores/patologia , Criança , Pré-EscolarRESUMO
Targeted genome capture combined with next-generation sequencing was used to analyze 2.9 Mb of the DFNB79 interval on chromosome 9q34.3, which includes 108 candidate genes. Genomic DNA from an affected member of a consanguineous family segregating recessive, nonsyndromic hearing loss was used to make a library of fragments covering the DFNB79 linkage interval defined by genetic analyses of four pedigrees. Homozygosity for eight previously unreported variants in transcribed sequences was detected by evaluating a library of 402,554 sequencing reads and was later confirmed by Sanger sequencing. Of these variants, six were determined to be polymorphisms in the Pakistani population, and one was in a noncoding gene that was subsequently excluded genetically from the DFNB79 linkage interval. The remaining variant was a nonsense mutation in a predicted gene, C9orf75, renamed TPRN. Evaluation of the other three DFNB79-linked families identified three additional frameshift mutations, for a total of four truncating alleles of this gene. Although TPRN is expressed in many tissues, immunolocalization of the protein product in the mouse cochlea shows prominent expression in the taper region of hair cell stereocilia. Consequently, we named the protein taperin.
Assuntos
Cromossomos Humanos Par 9/genética , Surdez/genética , Mutação , Proteínas/genética , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Códon sem Sentido , Consanguinidade , Surdez/metabolismo , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Células Ciliadas Auditivas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Dados de Sequência Molecular , Fases de Leitura Aberta , Paquistão , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , Distribuição TecidualRESUMO
This study elaborates the concept of green effectuation orientations (GEOs) to enhance the environmental performance of entrepreneurial SMEs based in the Jiangsu province of China. For this purpose, we collected the data from 328 employees of entrepreneurial SMEs via a survey and analyzed it through SEM. We evaluated the GEO concept on mindset and action-based views to operationalize the construct with all subdimensions fully. Our study illustrates some unexplored domains of entrepreneurship research and comes up with the findings that (GEOs) are positively correlated with environmental performance (EP), green innovation performance (GIP), and environmental management initiatives (EMI). Additionally, the findings of this research also unveil that EMI and GIP pave the way for EP, as both mediate the relationship between GEO and EP. Last but not the least, this research study also explained the effective mechanism through which CSR commitment as a moderator can affect the relationship between GEO and EP. The findings of this study expand the spheres of effectuation theory and come up with several exciting theoretical and managerial implications. Besides, it is the first of its kind to demonstrate that GEO could enhance GIP, EMI, and EP.