Computational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopia

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dc.authoridAslı Kutlu / 0000-0002-9169-388Xen_US
dc.authorscopusidAslı Kutlu / 57716458200
dc.authorwosidAslı Kutlu / AGG-7405-2022en_US
dc.contributor.authorGerlevik, Umut
dc.contributor.authorCangul, Hakan
dc.contributor.authorKutlu, Aslı
dc.contributor.authorSaygi, Ceren
dc.contributor.authorCaralan, Erdal Firat
dc.contributor.authorTopcu, Yasemin
dc.contributor.authorOzoren, Nesrin
dc.contributor.authorSezerman, Osman Ugur
dc.date.accessioned2022-06-02T10:51:10Z
dc.date.available2022-06-02T10:51:10Z
dc.date.issued2022en_US
dc.departmentİstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoenformatik ve Genetik Bölümüen_US
dc.description.abstractBackground Periventricular nodular heterotopia (PNH) is a cell migration disorder associated with mutations in Filamin-A (FLNA) gene on chromosome X. Majority of the individuals with PNHassociated FLNA mutations are female whereas liveborn males with FLNA mutations are very rare. Fetal viability of the males seems to depend on the severity of the variant. Splicing or severe truncations presumed loss of function of the protein product, lead to male lethality and only partial-loss-of-function variants are reported in surviving males. Those variants mostly manifest milder clinical phenotypes in females and thus avoid detection of the disease in females. Methods We describe a novel p.Arg484Gln variant in the FLNA gene by performing whole exome analysis on the index case, his one affected brother and his healthy non-consanguineous parents. The transmission of PNH from a clinically asymptomatic mother to two sons is reported in a fully penetrant classical X-linked dominant mode. The variant was verified via Sanger sequencing. Additionally, we investigated the impact of missense mutations reported in affected males on the FLNa protein structure, dynamics and interactions by performing molecular dynamics (MD) simulations to examine the disease etiology and possible compensative mechanisms allowing survival of the males. Results We observed that p.Arg484Gln disrupts the FLNa by altering its structural and dynamical properties including the flexibility of certain regions, interactions within the protein, and conformational landscape of FLNa. However, these impacts existed for only a part the MD trajectories and highly similar patterns observed in the other 12 mutations reported in the liveborn males validated this mechanism. Conclusion It is concluded that the variants seen in the liveborn males result in transient pathogenic effects, rather than persistent impairments. By this way, the protein could retain its function occasionally and results in the survival of the males besides causing the disease.en_US
dc.identifier.citationGerlevik U, Saygı C, Cangül H, Kutlu A, Çaralan EF, Topçu Y, Özören N, Sezerman OU. Computational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopia. PLoS One. 2022 May 25;17(5):e0265400. doi: 10.1371/journal.pone.0265400. PMID: 35613087; PMCID: PMC9132340.en_US
dc.identifier.doi10.1371/journal.pone.0265400en_US
dc.identifier.issn1932-6203en_US
dc.identifier.issue5en_US
dc.identifier.pmid35613087en_US
dc.identifier.scopus2-s2.0-85130882345en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttp://doi.org/10.1371/journal.pone.0265400
dc.identifier.urihttps://hdl.handle.net/20.500.12713/2788
dc.identifier.volume17en_US
dc.identifier.wosWOS:000944284700019en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorKutlu, Aslı
dc.language.isoenen_US
dc.publisherPMCen_US
dc.relation.ispartofPLoS Oneen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleComputational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopiaen_US
dc.typeArticleen_US

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