Mutations in filamin 1 Prevent Migration of Cerebral Cortical Neurons in Human Periventricular Heterotopia

Fox, Jeremy W.; Lamperti, Edward D.; Ekşioğlu, Yaman Z.; Hong, Susan E.; Feng, Yuanyi; Graham, Donna; Scheffer, Ingrid E.; Dobyns, William B.; Hirsch, Betsy A.; Radtke, Rodney A.; Berkovic, Samuel F.; Huttenlocher, Peter R.; Walsh, Christopher A.

doi:10.1016/s0896-6273(00)80651-0

Cited by 805 publications

(592 citation statements)

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“…We conclude that OPD1, OPD2, FMD and MNS are allelic conditions 12 , which we collectively term 'OPD-spectrum disorders' . All (17 of 17) mutations reported here, in contrast with a small minority (2 of 14) associated with PVNH 3,5,6 , conserve the reading frame and are predicted to produce full-length filamin A. We compared the structure of filamin A and the distribution of mutations in the ABD with selected proteins containing a homologous domain (Fig.…”

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“…After excluding 24 other genes, we examined FLNA. Mutations in FLNA (predominantly nonsense and frameshift mutations but including two missense mutations) lead to the clinically unrelated neuronal migration disorder PVNH 3,5,6 . FLNA comprises 48 exons and encodes a protein of 280 kDa that possesses an N-terminal actin-binding domain (ABD) containing two calponin homology domains (CHD1 and CHD2) and an extended region made up of 24 repeated rod subdomains that bind to multiple proteins (refs.…”

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“…Second, 12 of 14 mutations causing PVNH predict protein truncation and/or mRNA instability and are assumed to lead to loss of function 3,5,6 , whereas 17 of 17 mutations causing OPD-spectrum disorders conserve the reading frame, compatible with specific altered functions. Third, the distinct genotype-phenotype correlations that we observe (Table 1) imply that different mutations confer different altered functions.…”

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

et al. 2003

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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 messengers 1,2 . 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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Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

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“…22). On the other hand, mutations in FLNA are the only other identified cause of periventricular heterotopia, but unlike ARFGEF2, FLNA is not associated with microcephaly, and it encodes an actinbinding protein 23 . Thus, the current findings emphasize the crucial, if not yet widely recognized, role of vesicular trafficking in human embryonic development and raise the possibility that the enlarging superfamily of ARFGEF proteins may have evolved more specialized and overlapping functions than suspected [2][3][4][5][6] .…”

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Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

et al. 2003

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Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia 1 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northernblot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and β-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.Autosomal recessive periventricular heterotopia with microcephaly (ARPHM) is a severe malformation of the cerebral cortex, characterized by severe developmental delay and recurrent infections 1 . No anomalies extrinsic to the CNS, such as dysmorphic features or grossly abnormal endocrine or other conditions, have been observed in individuals with ARPHM. Magnetic resonance imaging of the brains of affected individuals shows notable periventricular heterotopia, resulting from the failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex ( Fig. 1a-d). Abnormal magnetic resonance image signals in subcortical white matter and elsewhere also suggest a delay in the normal myelination by glial cells.An initial genome-wide screen at 10-cM intervals of two Turkish families with ARPHM identified shared homozygosity at a single locus on chromosome 20q11.21-13.2, which we refined by further marker analysis (Fig. 1e,f). Because the two families had indistinguishable clinical and radiographic features, we assumed that they had an allelic disorder and summed their linkage results. The ARPHM region (66.16-77.75 cM on chromosome 20) that was identical by descent in each of the two families yielded a summed multipoint lod score of 4.41 (Fig. 1g). Two-point analyses gave combined maximal lod scores of 3.28 (pedigree 1 = 1.53 and pedigree 2 = 1.75) at marker D20S109 (Fig. 1h).We sequenced several candidate genes in the minimal linked region and found a different deleterious mutation in ARFGEF2 (encod...

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“…FLNA mutations can result in lossof-function or alterations in filamin A function (Robertson 2005). The former was seen in bilateral periventricular nodular heterotopia (PVNH) (OMIM: 300049) (Fox et al 1998), and the latter has been reported in OPD-spectrum disorders such as OPD I, OPD II, frontometaphyseal dysplasia and MelnickNeedles syndrome. Genotype-phenotype correlation is relatively clear between Melnick-Needles syndrome and OPD II, but is not always so between OPD I and OPD II.…”

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A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype–genotype correlation

et al. 2007

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We report the case of a 12 year-old boy with oto-palato-digital syndrome type II (OPD II). He had various anomalies at birth, including bilateral cataracts, bilateral glaucoma, bilateral severe hearing impairment, congenital heart defect, umbilical herniation, bowed extremities and constrictions of various joints. These clinical features and whole body X-ray findings were compatible with OPD II. However, his ocular disorders such as congenital cataract and glaucoma, and congenital heart defect have never been associated with OPD II as far as we know. His chromosomal analysis revealed normal karyotype, 46,XY. Analysis of the filamin A gene using a standard PCRdirect sequencing method determined a C586T (Arg196Trp) missense mutation in exon 3. Interestingly, the same C586T mutation was reported previously in a patient with OPD I (mild form). Thus, phenotype-genotype correlation of OPD is lacking in those patients. Further clinical and genetic studies are needed to clarify the relationship between phenotypes and genotypes, or to identify other factor(s) that influence the clinical features of this syndrome.

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Mutations in filamin 1 Prevent Migration of Cerebral Cortical Neurons in Human Periventricular Heterotopia

Cited by 805 publications

References 54 publications

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

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

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype–genotype correlation

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