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

Stephen P. Robertson, Stephen R.F. Twigg, Andrew J. Sutherland-Smith, Valérie Biancalana, Robert J. Gorlin, Denise Horn, Susan J. Kenwrick, Chong A. Kim, Eva Morava-Kozicz, Ruth Newbury-Ecob, Karen H. Ørstavik, Oliver W.J. Quarrell, Charles E. Schwartz, Deborah J. Shears, Mohnish Suri, John Kendrick-Jones, C. Bacino, K. Becker, J. Clayton-Smith, M. Giovannucci-UzielliD. 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, O. M. Wilkie

Research output: Contribution to journalArticle

278 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)487-491
Number of pages5
JournalNature Genetics
Volume33
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

Filamins
Genetic Databases
Cytoskeletal Proteins
Mutation
Genes
Periventricular Nodular Heterotopia
Group II Malformations of Cortical Development
Osteochondrodysplasias
X Chromosome Inactivation
Reading Frames
Viscera
Organogenesis
Cell Shape
Cytoskeleton
Actin Cytoskeleton
Skeleton
Integrins
Embryonic Development
Cell Movement
Actins

ASJC Scopus subject areas

  • Genetics

Cite this

Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., ... Wilkie, O. M. (2003). Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nature Genetics, 33(4), 487-491. https://doi.org/10.1038/ng1119

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. / Robertson, Stephen P.; Twigg, Stephen R.F.; Sutherland-Smith, Andrew J.; Biancalana, Valérie; Gorlin, Robert J.; Horn, Denise; Kenwrick, Susan J.; Kim, Chong A.; Morava-Kozicz, Eva; Newbury-Ecob, Ruth; Ørstavik, Karen H.; Quarrell, Oliver W.J.; Schwartz, Charles E.; Shears, Deborah J.; Suri, Mohnish; Kendrick-Jones, John; Bacino, C.; Becker, K.; Clayton-Smith, J.; Giovannucci-Uzielli, M.; Goh, D.; Grange, D.; Krajewska-Welasek, M.; Lacombe, D.; Morris, C.; Odent, S.; Savarirayan, R.; Stratton, R.; Superti-Furga, A.; Verloes, A.; Vigneron, J.; Wilcox, W.; Winter, R.; Young, K.; Wilkie, O. M.

In: Nature Genetics, Vol. 33, No. 4, 01.04.2003, p. 487-491.

Research output: Contribution to journalArticle

Robertson, SP, Twigg, SRF, Sutherland-Smith, AJ, Biancalana, V, Gorlin, RJ, Horn, D, Kenwrick, SJ, Kim, CA, Morava-Kozicz, E, Newbury-Ecob, R, Ørstavik, KH, Quarrell, OWJ, Schwartz, CE, Shears, DJ, Suri, M, Kendrick-Jones, J, Bacino, C, Becker, K, Clayton-Smith, J, Giovannucci-Uzielli, M, Goh, D, Grange, D, Krajewska-Welasek, M, Lacombe, D, Morris, C, Odent, S, Savarirayan, R, Stratton, R, Superti-Furga, A, Verloes, A, Vigneron, J, Wilcox, W, Winter, R, Young, K & Wilkie, OM 2003, 'Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans', Nature Genetics, vol. 33, no. 4, pp. 487-491. https://doi.org/10.1038/ng1119
Robertson SP, Twigg SRF, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nature Genetics. 2003 Apr 1;33(4):487-491. https://doi.org/10.1038/ng1119
Robertson, Stephen P. ; Twigg, Stephen R.F. ; Sutherland-Smith, Andrew J. ; Biancalana, Valérie ; Gorlin, Robert J. ; Horn, Denise ; Kenwrick, Susan J. ; Kim, Chong A. ; Morava-Kozicz, Eva ; Newbury-Ecob, Ruth ; Ørstavik, Karen H. ; Quarrell, Oliver W.J. ; Schwartz, Charles E. ; Shears, Deborah J. ; Suri, Mohnish ; Kendrick-Jones, John ; Bacino, C. ; Becker, K. ; Clayton-Smith, J. ; Giovannucci-Uzielli, M. ; Goh, D. ; Grange, D. ; Krajewska-Welasek, M. ; Lacombe, D. ; Morris, C. ; Odent, S. ; Savarirayan, R. ; Stratton, R. ; Superti-Furga, A. ; Verloes, A. ; Vigneron, J. ; Wilcox, W. ; Winter, R. ; Young, K. ; Wilkie, O. M. / Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. In: Nature Genetics. 2003 ; Vol. 33, No. 4. pp. 487-491.
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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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AU - Twigg, Stephen R.F.

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AU - Biancalana, Valérie

AU - Gorlin, Robert J.

AU - Horn, Denise

AU - Kenwrick, Susan J.

AU - Kim, Chong A.

AU - Morava-Kozicz, Eva

AU - Newbury-Ecob, Ruth

AU - Ørstavik, Karen H.

AU - Quarrell, Oliver W.J.

AU - Schwartz, Charles E.

AU - Shears, Deborah J.

AU - Suri, Mohnish

AU - Kendrick-Jones, John

AU - Bacino, C.

AU - Becker, K.

AU - Clayton-Smith, J.

AU - Giovannucci-Uzielli, M.

AU - Goh, D.

AU - Grange, D.

AU - Krajewska-Welasek, M.

AU - Lacombe, D.

AU - Morris, C.

AU - Odent, S.

AU - Savarirayan, R.

AU - Stratton, R.

AU - Superti-Furga, A.

AU - Verloes, A.

AU - Vigneron, J.

AU - Wilcox, W.

AU - Winter, R.

AU - Young, K.

AU - Wilkie, O. M.

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