Journal Article

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

Volney L. Sheen, Peter H. Dixon, Jeremy W. Fox, Susan E. Hong, Lucy Kinton, Sanjay M. Sisodiya, John S. Duncan, Francois Dubeau, Ingrid E. Scheffer, Steven C. Schachter, Andrew Wilner, Ruth Henchy, Peter Crino, Kazuhiro Kamuro, Frances DiMario, Michel Berg, Ruben Kuzniecky, Andrew J. Cole, Edward Bromfield, Michael Biber, Donald Schomer, James Wheless, Kenneth Silver, Ganeshwaran H. Mochida, Samuel F. Berkovic, Fred Andermann, Eva Andermann, William B. Dobyns, Nicholas W. Wood and Christopher A. Walsh

in Human Molecular Genetics

Volume 10, issue 17, pages 1775-1783
Published in print August 2001 | ISSN: 0964-6906
Published online August 2001 | e-ISSN: 1460-2083 | DOI:
Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females

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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.

Journal Article.  5977 words.  Illustrated.

Subjects: Genetics and Genomics

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