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Human Molecular Genetics, 2001, Vol. 10, No. 17 1775-1783
© 2001 Oxford University Press

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females

Volney L. Sheen1,18, Peter H. Dixon2, Jeremy W. Fox1,3, Susan E. Hong1, Lucy Kinton2, Sanjay M. Sisodiya4, John S. Duncan4, Francois Dubeau5, Ingrid E. Scheffer6, Steven C. Schachter1, Andrew Wilner7, Ruth Henchy8, Peter Crino9, Kazuhiro Kamuro10, Frances DiMario11, Michel Berg12, Ruben Kuzniecky13, Andrew J. Cole14,18, Edward Bromfield15, Michael Biber1, Donald Schomer1, James Wheless16, Kenneth Silver17, Ganeshwaran H. Mochida1,18, Samuel F. Berkovic6, Fred Andermann5, Eva Andermann5, William B. Dobyns19, Nicholas W. Wood2 and Christopher A. Walsh1,3,+

1Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA, 2Neurogenetics Unit, Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK, 3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA, 4Epilepsy Group, Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK, 5Department of Neurogenetics and Epilepsy Service, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, 6Department of Neurology, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Melbourne, Victoria, Australia, 7Neurology, Americas Building, Newport, RI 02840, USA, 8Department of Neurology, Medical Clinic, Pensacola, FL, USA, 9Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA, 10Department of Pediatrics, Kokubu Seikyo Hospital, Kogoshima, Japan, 11Department of Pediatrics, University of Connecticut, Farmington, CT, USA, 12Department of Neurology, University of Rochester, Rochester, NY, USA, 13Department of Neurology, University of Alabama, Birmingham, AL, USA, 14Epilepsy Service, Massachusetts General Hospital, Boston, MA, USA, 15Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA, 16Department of Pediatric Neurology, University of Texas, Houston, TX, USA, 17Department of Pediatric Neurology, Loyola University Medical Center, Chicago, IL, USA, 18Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA, 19Department of Human Genetics, University of Chicago, Chicago, IL, USA

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

+ To whom correspondence should be addressed at: Room 816, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel: +1 617 667 0813; Fax: +1 617 667 0815; Email: cwalsh@caregroup.harvard.eduThe authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors


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