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Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Nature Genetics volume 33, pages 487–491 (2003)Cite this article

Abstract

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers1,2. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick–Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3–6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.

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Figure 1: Phenotype of the OPD-spectrum disorders caused by mutations in FLNA.
Figure 2: Structure of filamin A and identification of mutations in the OPD-spectrum disorders.
Figure 3: Sequence conservation and distribution of missense mutations in the CHD2 of seven human proteins.
Figure 4: Model of the CHD2 domain of filamin A based on the equivalent structures for dystrophin22 and β-spectrin23.
Figure 5: Skewing of X chromosome inactivation in the OPD-spectrum disorders.

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Acknowledgements

We are grateful to the individuals, families and members of the MNS Support Group who participated in this research, A. McCoy for discussions on filamin A structure, M. Cossee and B. Hane for sharing unpublished results and N. Elanko, I. Taylor, S. Butler and K. Clark for technical assistance. This work was supported by a Nuffield Medical Fellowship (S.P.R.) and a Wellcome Trust Senior Research Fellowship in Clinical Science (A.O.M.W.).

Author information

Author notes

  1. Stephen P. Robertson

    Present address: University of Minnesota, USA

  2. K. Young

    Present address: Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand

Authors and Affiliations

  1. Weatherall Institute of Molecular Medicine, Room 304, The John Radcliffe, Headley Way, Oxford, OX3 9DS, UK

    Stephen P. Robertson, Stephen R.F. Twigg & Andrew O.M. Wilkie

  2. MRC Laboratory of Molecular Biology, Cambridge, UK

    Andrew J. Sutherland-Smith & John Kendrick-Jones

  3. Laboratoire de Diagnostic Génétique, Faculté de Médecine et CHRU, Strasbourg, France

    Valérie Biancalana

  4. Department of Oral Pathology and Genetics, University of Minnesota, Minneapolis, Minnesota, USA

    Robert J. Gorlin

  5. Institut für Humangenetik, Humboldt University, Berlin, Germany

    Denise Horn

  6. Cambridge Institute for Medical Research, Addenbrookes Hospital, Cambridge, UK

    Susan J. Kenwrick

  7. Pediatria-Genética, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    Chong A. Kim

  8. Department of Medical Genetics, University of Pécs, Pécs, Hungary

    Eva Morava

  9. Clinical Genetics Service, United Bristol Hospitals Trust, Bristol, UK

    Ruth Newbury-Ecob

  10. Institute Group of Clinical Medicine, University of Oslo, Norway

    Karen H. Ørstavik

  11. North Trent Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK

    Oliver W.J. Quarrell

  12. Greenwood Genetics Center, Greenwood, South Carolina, USA

    Charles E. Schwartz

  13. Clinical and Molecular Genetics Unit, The Institute of Child Health, London, UK

    Deborah J. Shears

  14. Clinical Genetics Service, City Hospital, Nottingham, UK

    Mohnish Suri

  15. Baylor College of Medicine, USA

    C. Bacino

  16. Kennedy Galton Centre, UK

    K. Becker

  17. St. Mary's Hospital, UK

    J. Clayton-Smith

  18. University of Florence, Italy

    M. Giovannucci-Uzielli

  19. Johns Hopkins University, USA

    D. Goh

  20. Washington University, USA

    D. Grange

  21. The Children's Memorial Health Institute, Poland

    M. Krajewska-Welasek

  22. Genetique Medicale-Hôpital Pellegrin-Enfants, France

    D. Lacombe

  23. University of Nevada, USA

    C. Morris

  24. Hôpital Pontchaillou, France

    S. Odent

  25. Genetic Health Services Victoria, Australia

    R. Savarirayan

  26. The University of Texas, USA

    R. Stratton

  27. Centre Hospitalier Universitaire Vaudois, Switzerland

    A. Superti-Furga

  28. Hôpital Robert Debré, France

    A. Verloes

  29. Service de Maternité Regionale “A. Pinard”, France

    J. Vigneron

  30. Cedars-Sinai Medical Center Los Angeles, USA

    W. Wilcox

  31. Institute of Child Health, UK

    R. Winter

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Consortia

The OPD-spectrum Disorders Clinical Collaborative Group

  • C. Bacino
  • , K. Becker
  • , J. Clayton-Smith
  • , M. Giovannucci-Uzielli
  • , D. Goh
  • , D. Grange
  • , M. Krajewska-Welasek
  • , D. Lacombe
  • , C. Morris
  • , S. Odent
  • , R. Savarirayan
  • , R. Stratton
  • , A. Superti-Furga
  • , A. Verloes
  • , J. Vigneron
  • , W. Wilcox
  • , R. Winter
  •  & K. Young

Corresponding authors

Correspondence to Stephen P. Robertson or Andrew O.M. Wilkie.

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The authors declare no competing financial interests.

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Robertson, S., Twigg, S., Sutherland-Smith, A. et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 33, 487–491 (2003). https://doi.org/10.1038/ng1119

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