Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans (original) (raw)

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.

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Figure 2: Structure of filamin A and identification of mutations in the OPD-spectrum disorders.

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Figure 3: Sequence conservation and distribution of missense mutations in the CHD2 of seven human proteins.

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Figure 4: Model of the CHD2 domain of filamin A based on the equivalent structures for dystrophin22 and β-spectrin23.

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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

Authors

  1. Stephen P. Robertson
  2. Stephen R.F. Twigg
  3. Andrew J. Sutherland-Smith
  4. Valérie Biancalana
  5. Robert J. Gorlin
  6. Denise Horn
  7. Susan J. Kenwrick
  8. Chong A. Kim
  9. Eva Morava
  10. Ruth Newbury-Ecob
  11. Karen H. Ørstavik
  12. Oliver W.J. Quarrell
  13. Charles E. Schwartz
  14. Deborah J. Shears
  15. Mohnish Suri
  16. John Kendrick-Jones
  17. Andrew O.M. Wilkie

Consortia

The OPD-spectrum Disorders Clinical Collaborative Group

Corresponding authors

Correspondence toStephen P. Robertson or Andrew O.M. Wilkie.

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Competing interests

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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