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 BiberDonald Schomer, James Wheless, Kenneth Silver, Ganeshwaran H. Mochida, Samuel F. Berkovic, Fred Andermann, Eva Andermann, William B. Dobyns, Nicholas W. Wood, Christopher A. Walsh

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1775-1783
Number of pages9
JournalHuman molecular genetics
Volume10
Issue number17
StatePublished - Aug 15 2001

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Periventricular Nodular Heterotopia
Filamins
Mutation
Genes
Pedigree
Group II Malformations of Cortical Development
Neurons
X-Linked Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Sheen, V. L., Dixon, P. H., Fox, J. W., Hong, S. E., Kinton, L., Sisodiya, S. M., ... Walsh, C. A. (2001). Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Human molecular genetics, 10(17), 1775-1783.

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. / Sheen, Volney L.; Dixon, Peter H.; Fox, Jeremy W.; Hong, Susan E.; Kinton, Lucy; Sisodiya, Sanjay M.; Duncan, John S.; Dubeau, Francois; Scheffer, Ingrid E.; Schachter, Steven C.; Wilner, Andrew; Henchy, Ruth; Crino, Peter; Kamuro, Kazuhiro; DiMario, Frances; Berg, Michel; Kuzniecky, Ruben; Cole, Andrew J.; Bromfield, Edward; Biber, Michael; Schomer, Donald; Wheless, James; Silver, Kenneth; Mochida, Ganeshwaran H.; Berkovic, Samuel F.; Andermann, Fred; Andermann, Eva; Dobyns, William B.; Wood, Nicholas W.; Walsh, Christopher A.

In: Human molecular genetics, Vol. 10, No. 17, 15.08.2001, p. 1775-1783.

Research output: Contribution to journalArticle

Sheen, VL, Dixon, PH, Fox, JW, Hong, SE, Kinton, L, Sisodiya, SM, Duncan, JS, Dubeau, F, Scheffer, IE, Schachter, SC, Wilner, A, Henchy, R, Crino, P, Kamuro, K, DiMario, F, Berg, M, Kuzniecky, R, Cole, AJ, Bromfield, E, Biber, M, Schomer, D, Wheless, J, Silver, K, Mochida, GH, Berkovic, SF, Andermann, F, Andermann, E, Dobyns, WB, Wood, NW & Walsh, CA 2001, 'Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females', Human molecular genetics, vol. 10, no. 17, pp. 1775-1783.
Sheen VL, Dixon PH, Fox JW, Hong SE, Kinton L, Sisodiya SM et al. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Human molecular genetics. 2001 Aug 15;10(17):1775-1783.
Sheen, Volney L. ; Dixon, Peter H. ; Fox, Jeremy W. ; Hong, Susan E. ; Kinton, Lucy ; Sisodiya, Sanjay M. ; Duncan, John S. ; Dubeau, Francois ; Scheffer, Ingrid E. ; Schachter, Steven C. ; Wilner, Andrew ; Henchy, Ruth ; Crino, Peter ; Kamuro, Kazuhiro ; DiMario, Frances ; Berg, Michel ; Kuzniecky, Ruben ; Cole, Andrew J. ; Bromfield, Edward ; Biber, Michael ; Schomer, Donald ; Wheless, James ; Silver, Kenneth ; Mochida, Ganeshwaran H. ; Berkovic, Samuel F. ; Andermann, Fred ; Andermann, Eva ; Dobyns, William B. ; Wood, Nicholas W. ; Walsh, Christopher A. / Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. In: Human molecular genetics. 2001 ; Vol. 10, No. 17. pp. 1775-1783.
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abstract = "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.",
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T1 - Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females

AU - Sheen, Volney L.

AU - Dixon, Peter H.

AU - Fox, Jeremy W.

AU - Hong, Susan E.

AU - Kinton, Lucy

AU - Sisodiya, Sanjay M.

AU - Duncan, John S.

AU - Dubeau, Francois

AU - Scheffer, Ingrid E.

AU - Schachter, Steven C.

AU - Wilner, Andrew

AU - Henchy, Ruth

AU - Crino, Peter

AU - Kamuro, Kazuhiro

AU - DiMario, Frances

AU - Berg, Michel

AU - Kuzniecky, Ruben

AU - Cole, Andrew J.

AU - Bromfield, Edward

AU - Biber, Michael

AU - Schomer, Donald

AU - Wheless, James

AU - Silver, Kenneth

AU - Mochida, Ganeshwaran H.

AU - Berkovic, Samuel F.

AU - Andermann, Fred

AU - Andermann, Eva

AU - Dobyns, William B.

AU - Wood, Nicholas W.

AU - Walsh, Christopher A.

PY - 2001/8/15

Y1 - 2001/8/15

N2 - 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.

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