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  • 1
    Online Resource
    Online Resource
    In silico Analysis of PRODH Mutations and their biological significance in disease etiology
    Abasyn University ; 2022
    In:  Abasyn Journal Life Sciences , No. Volume 5 Issue 1 ( 2022-6-30), p. 72-83
    Details
    In: Abasyn Journal Life Sciences, Abasyn University, , No. Volume 5 Issue 1 ( 2022-6-30), p. 72-83
    Abstract: In the present study, we performed in silico analysis on all reported mutations of PRODH in order to investigate their biological significance. 3D models of wildtype and mutant PRODH were predicted using I-TASSER. Protein-protein docking was done with Cluspro, while protein-substrate docking was done with Auto Dock tools. Alignment of 3D models (various mutant with wildtype) revealed that Arg185Gln (73.83%) and Gln19Term (6.25%) had the highest and lowest similarity indices, respectively. Enzyme pocket prediction identified the second largest active site pocket containing substrate proline binding residues Leu527, Tyr548, and Arg563. Moreover, docking of mutant and wildtype PRODH with its close interactor ALDH4A1 showed differences with respect to position and nature of interacting amino acids residues. We observed that the nature of amino acid substitution and the number of bonds affect the binding of proline molecule with enzyme, and therefore, affect its biological activity. Keywords: PRODH, proline dehydrogenase enzyme, in silico analysis, modeling and docking, biological significance
    Type of Medium: Online Resource
    ISSN: 2663-1040 , 2616-9754
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.34091/AJLS.5.1
    DOI: 10.34091/ajls
    DOI: 10.34091/AJLS.5.1.7
    Language: English
    Publisher: Abasyn University
    Publication Date: 2022
    detail.hit.zdb_id: 3023973-4
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  • 2
    Online Resource
    Online Resource
    Table_2.DOCX
    Frontiers Media SA ; 2023
    In:  Frontiers in Neurology Vol. 14 ( 2023-5-25)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 14 ( 2023-5-25)
    Abstract: Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70. Methods The current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants. Results and discussion Genetic analysis using whole exome sequencing in these families identified two novel mutations in the NSUN2 (NM_017755.5). Family-A segregated a novel missense variant c.953A & gt;C; p.Tyr318Ser in exon-9 of the NSUN2 . The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of NSUN2 known as “SAM-dependent methyltransferase RsmB/NOP2-type”. Whereas in family B, we identified a novel splice site variant c.97-1G & gt;C that affects the splice acceptor site of NSUN2 . The identified splice variant (c.97-1G & gt;C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs * 16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of NSUN2 missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of NSUN2 function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of NSUN2 to be involved in ID and its genetic heterogeneity in the Pakistani population.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fneur.2023.1168307
    DOI: 10.3389/fneur.2023.1168307.s001
    DOI: 10.3389/fneur.2023.1168307.s002
    DOI: 10.3389/fneur.2023.1168307.s003
    DOI: 10.3389/fneur.2023.1168307.s004
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2564214-5
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  • 3
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    Online Resource
    A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family
    Frontiers Media SA ; 2023
    In:  Frontiers in Endocrinology Vol. 14 ( 2023-3-7)
    Details
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 14 ( 2023-3-7)
    Abstract: Isolated growth hormone deficiency (IGHD) is caused by a severe shortage or absence of growth hormone (GH), which results in aberrant growth and development. Patients with IGHD type IV (IGHD4) have a short stature, reduced serum GH levels, and delayed bone age. Objectives To identify the causative mutation of IGHD in a consanguineous family comprising four affected patients with IGHD4 (MIM#618157) and explore its functional impact in silico . Methods Clinical and radiological studies were performed to determine the phenotypic spectrum and hormonal profile of the disease, while whole-exome sequencing (WES) and Sanger sequencing were performed to identify the disease-causing mutation. In-silico studies involved protein structural modeling and docking, and molecular dynamic simulation analyses using computational tools. Finally, data from the Qatar Genome Program (QGP) were screened for the presence of the founder variant in the Qatari population. Results All affected individuals presented with a short stature without gross skeletal anomalies and significantly reduced serum GH levels. Genetic mapping revealed a homozygous nonsense mutation [NM_000823:c.G214T:p.(Glu72*)] in the third exon of the growth-hormone-releasing hormone receptor gene GHRHR (MIM#139191) that was segregated in all patients. The substituted amber codon (UAG) seems to truncate the protein by deleting the C-terminus GPCR domain, thus markedly disturbing the GHRHR receptor and its interaction with the growth hormone-releasing hormone. Conclusion These data support that a p.Glu72* founder mutation in GHRHR perturbs growth hormone signaling and causes IGHD type IV. In-silico and biochemical analyses support the pathogenic effect of this nonsense mutation, while our comprehensive phenotype and hormonal profiling has established the genotype–phenotype correlation. Based on the current study, early detection of GHRHR may help in better therapeutic intervention.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    URL: Article
    DOI: 10.3389/fendo.2023.1066182
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2592084-4
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