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

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.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

“…8,13 Our demonstration of both null and hypomorphic alleles resulting in XL-PH-connective tissue-vascular presentations suggests that there is little at the molecular level to separate the mutations underlying these presentations from those reported to lead to undifferentiated XL-PH in large, previously reported, cohorts. 14,15 The mutations identified in subjects F1-F6 are non-sense, splice site or frameshift mutations that, if they do not lead to non-sense mediated mRNA decay (F1; Figure 1f), are otherwise predicted to produce proteins missing key domains such as integrin binding sites and the homodimerization domain in FLNA. They can therefore be confidently considered to be functionally null alleles.…”

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

“…Humans with disruption in the VZ of the telencephalon carry PH primarily composed of later-born neurons (Ferland et al, 2009). Mutations in either of two human genes, fi lamin A (FLNA) or ADPribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Sheen et al, 2001(Sheen et al, , 2003. In the mouse, the loss of FlnA function aff ects cell adhesion, disrupts the VZ and impairs neuronal migration.…”

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

“…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.…”

“…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.…”

“…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.…”