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1.
PLoS Genet ; 18(3): e1010114, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35298461

RESUMO

The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.


Assuntos
Microcefalia , Transtornos do Neurodesenvolvimento , Animais , Humanos , Camundongos , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo
2.
Curr Microbiol ; 79(2): 48, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34982246

RESUMO

This study aimed to characterize the whole genome of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) isolated from an oropharyngeal swab specimen of a Pashtun Pakistani patient using next-generation sequencing. Upon comparing the SARS-CoV2 genome to the reference genome, a total of 10 genetic variants were identified. Among the 10 genetic variants, 1 missense mutation (c.1139A > G, p.Lys292Glu) in the Open Reading Frame 1ab (ORF1ab) positioned at 112 in the non-structural protein 2 (NSP2) was found to be unique. Phylogenetic analysis (n = 84) revealed that the current SARS-CoV2 genome was closely clustered with 8 Pakistani strains belonging to Punjab, Federal Capital, Azad Jammu and Kashmir (AJK), and Khyber Pakhtunkhwa (KP). In addition, the current SARS-CoV2 genome was very similar to the genome of SARS-CoV2 reported from Guam, Taiwan, India, the USA, and France. Overall, this study reports a slight mismatch in the SARS-CoV2 genome, indicating the presence of a single unique missense mutation. However, phylogenetic analysis revealed that the current SARS-CoV2 genome was closely clustered with 8 other Pakistani strains.


Assuntos
COVID-19 , RNA Viral , Genoma Viral , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Paquistão , Filogenia , SARS-CoV-2
3.
BMC Med Genomics ; 14(1): 211, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452636

RESUMO

BACKGROUND: Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder. METHODS: In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175. RESULTS: In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165. CONCLUSION: These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.


Assuntos
Deficiência Intelectual
4.
Hum Genet ; 137(9): 735-752, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167849

RESUMO

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.


Assuntos
Genes Recessivos , Marcadores Genéticos , Deficiência Intelectual/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Adulto , Consanguinidade , Família , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/complicações , Linhagem
5.
Am J Hum Genet ; 95(6): 721-8, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480035

RESUMO

Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.


Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas dos Microfilamentos/genética , Proteínas Nucleares/genética , Deleção de Sequência , Adolescente , Adulto , Sequência de Bases , Transtornos Cromossômicos/fisiopatologia , Estudos de Coortes , Consanguinidade , Egito , Exoma/genética , Feminino , Forminas , Genes Recessivos , Ligação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Paquistão , Linhagem , Análise de Sequência de DNA
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