Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA
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| 024 | 7 | 0 | |a 10.1007/s00109-015-1261-7 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00109-015-1261-7 | ||
| 245 | 0 | 0 | |a Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA |h [Elektronische Daten] |c [Margriet van Kogelenberg, Alice Clark, Zandra Jenkins, Tim Morgan, Ananda Anandan, Gregory Sawyer, Matthew Edwards, Tracy Dudding, Tessa Homfray, Bruce Castle, John Tolmie, Fiona Stewart, Emma Kivuva, Daniela Pilz, Michael Gabbett, Andrew Sutherland-Smith, Stephen Robertson] |
| 520 | 3 | |a Filamin 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. Key messages: • Mutations in the X-linked gene FLNA cause a spectrum of syndromes. • Genotype-phenotype correlations are emerging but still remain unclear. • C-term mutations can confer male lethality, survival or connective tissue defects. • Mutations leading to the latter affect filamin dimerisation. • This deficit is compensated for by remotely acting domains elsewhere in FLNA. | |
| 540 | |a Springer-Verlag Berlin Heidelberg, 2015 | ||
| 690 | 7 | |a Filamin A |2 nationallicence | |
| 690 | 7 | |a Periventricular neuronal heterotopia |2 nationallicence | |
| 690 | 7 | |a Dimerisation |2 nationallicence | |
| 700 | 1 | |a van Kogelenberg |D Margriet |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | |
| 700 | 1 | |a Clark |D Alice |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | |
| 700 | 1 | |a Jenkins |D Zandra |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | |
| 700 | 1 | |a Morgan |D Tim |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | |
| 700 | 1 | |a Anandan |D Ananda |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | |
| 700 | 1 | |a Sawyer |D Gregory |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | |
| 700 | 1 | |a Edwards |D Matthew |u Hunter Genetics, Newcastle, Australia |4 aut | |
| 700 | 1 | |a Dudding |D Tracy |u Hunter Genetics, Newcastle, Australia |4 aut | |
| 700 | 1 | |a Homfray |D Tessa |u Department of Clinical Genetics, St George's Hospital, Tooting, London, UK |4 aut | |
| 700 | 1 | |a Castle |D Bruce |u Wessex Regional Genetics Service, Southampton, UK |4 aut | |
| 700 | 1 | |a Tolmie |D John |u Fergusson-Smith Centre for Clinical Genetics, Glasgow, UK |4 aut | |
| 700 | 1 | |a Stewart |D Fiona |u Clinical Genetics Service, Belfast City Hospital, Belfast, UK |4 aut | |
| 700 | 1 | |a Kivuva |D Emma |u Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK |4 aut | |
| 700 | 1 | |a Pilz |D Daniela |u Institute of Medical Genetics, University Hospital of Wales, Cardiff University, Cardiff, UK |4 aut | |
| 700 | 1 | |a Gabbett |D Michael |u Genetic Health Queensland, Royal Brisbane and Women's Hospital and School of Medicine, Griffith University, Gold Coast, Australia |4 aut | |
| 700 | 1 | |a Sutherland-Smith |D Andrew |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | |
| 700 | 1 | |a Robertson |D Stephen |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | |
| 773 | 0 | |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/7(2015-07-01), 773-782 |x 0946-2716 |q 93:7<773 |1 2015 |2 93 |o 109 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00109-015-1261-7 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00109-015-1261-7 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a van Kogelenberg |D Margriet |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Clark |D Alice |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Jenkins |D Zandra |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Morgan |D Tim |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Anandan |D Ananda |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Sawyer |D Gregory |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Edwards |D Matthew |u Hunter Genetics, Newcastle, Australia |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Dudding |D Tracy |u Hunter Genetics, Newcastle, Australia |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Homfray |D Tessa |u Department of Clinical Genetics, St George's Hospital, Tooting, London, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Castle |D Bruce |u Wessex Regional Genetics Service, Southampton, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Tolmie |D John |u Fergusson-Smith Centre for Clinical Genetics, Glasgow, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Stewart |D Fiona |u Clinical Genetics Service, Belfast City Hospital, Belfast, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kivuva |D Emma |u Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Pilz |D Daniela |u Institute of Medical Genetics, University Hospital of Wales, Cardiff University, Cardiff, UK |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Gabbett |D Michael |u Genetic Health Queensland, Royal Brisbane and Women's Hospital and School of Medicine, Griffith University, Gold Coast, Australia |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Sutherland-Smith |D Andrew |u Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Robertson |D Stephen |u Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/7(2015-07-01), 773-782 |x 0946-2716 |q 93:7<773 |1 2015 |2 93 |o 109 | ||