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dc.contributor.authorvan Kogelenberg, Margriet
dc.contributor.authorClark, Alice R
dc.contributor.authorJenkins, Zandra
dc.contributor.authorMorgan, Tim
dc.contributor.authorAnandan, Ananda
dc.contributor.authorSawyer, Gregory M
dc.contributor.authorEdwards, Matthew
dc.contributor.authorDudding, Tracy
dc.contributor.authorHomfray, Tessa
dc.contributor.authorCastle, Bruce
dc.contributor.authorTolmie, John
dc.contributor.authorStewart, Fiona
dc.contributor.authorKivuva, Emma
dc.contributor.authorPilz, Daniela T
dc.contributor.authorGabbett, Michael
dc.contributor.authorSutherland-Smith, Andrew J
dc.contributor.authorRobertson, Stephen P
dc.date.accessioned2019-02-28T00:28:25Z
dc.date.available2019-02-28T00:28:25Z
dc.date.issued2015
dc.identifier.issn0946-2716
dc.identifier.doi10.1007/s00109-015-1261-7
dc.identifier.urihttp://hdl.handle.net/10072/101269
dc.description.abstractFilamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNAGly2593Glu repeat 16–24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherSpringer
dc.relation.ispartofpagefrom773
dc.relation.ispartofpageto782
dc.relation.ispartofissue7
dc.relation.ispartofjournalJournal of Molecular Medicine
dc.relation.ispartofvolume93
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchcode030499
dc.subject.fieldofresearchcode0304
dc.titleDiverse phenotypic consequences of mutations affecting the C-terminus of FLNA
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionPost-print
gro.hasfulltextFull Text
gro.griffith.authorGabbett, Michael T.


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