Periventricular heterotopia:: phenotypic heterogeneity and correlation with Filamin A mutations
Periventricular heterotopia:: phenotypic heterogeneity and correlation with Filamin A mutations
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DOI：
10.1093/brain/awl125
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发表时间：
2006-07-01
期刊：
影响因子：
14.5
通讯作者：
Guerrini, R.
中科院分区：
文献类型：
--
作者：
Parrini, E.;Ramazzotti, A.;Guerrini, R.
当神经元聚集在侧脑室或侧脑室正下方时，就会出现脑室周围异位（PH）。人细丝蛋白 A 基因 (FLNA) 突变与经典的 X 连锁双侧脑室周围结节性异位 (PNH) 相关，其特征为连续异位结节、巨大小脑延髓池、心血管畸形和癫痫。 FLNA 编码 F-肌动蛋白结合胞质磷蛋白，参与早期脑神经发生和神经元迁移。一种罕见的隐性双侧 PNH 伴有小头畸形和严重延迟，与 ADP-核糖基化因子鸟嘌呤核苷酸交换因子-2 (ARFGEF2) 基因的突变有关，该基因是从反高尔基体运输囊泡和膜所需的。然而，PH 是一种异质性疾病。我们研究了 182 名 PH 患者的临床和脑部 MRI，并根据其解剖分布和相关出生缺陷，确定了 15 种亚型。经典双侧 PNH 占最大组（98 名患者：54%）。 14 例其他表型（84 名患者：46%）包括伴有埃勒斯-当洛斯综合征 (EDS) 的 PNH、伴有海马畸形和小脑发育不全的颞枕 PNH、伴有额周裂或颞枕多小脑回的 PNH、伴有脑积水的后部 PNH、伴有小头畸形的 PNH、伴有额鼻发育不良的 PNH、PNH伴有肢体异常、伴有脆性 X 综合征的 PNH、具有模糊生殖器的 PNH、微结节性 PH、单侧 PNH、层流带状和线状 PH。我们对 120 名患者进行了 FLNA 突变分析，其中 72 名 (60%) 具有经典双侧 PNH 和 48 名 (40%) 其他 PH 表型，并在 40 名个体中鉴定出 25 个突变。此前未曾报道过十六种突变。在 35 名经典双侧 PNH 患者、三名伴有 EDS 的 PNH 患者和两名单侧 PNH 患者中发现了突变。二十一个突变是无义和移码，四个错义。导致蛋白质截短的突变的高发生率证实了功能丧失是该疾病的主要原因。 100% 的 X 连锁 PNH 家族病例（10 个家族：8 个经典双侧 PNH、1 个 EDS 和 1 个单侧 PH）以及 26% 散发的经典双侧 PNH 患者中发现 FLNA 突变。总体而言，49% 的经典双侧 PNH 患者发生突变，无论其是家族性还是散发性。然而，发现突变的机会存在极大的性别偏见，93% 的突变发生在女性，7% 发生在男性。在其他表型中发现 FLNA 突变的概率为 4%，但仅限于伴有 EDS 的 PNH 微小变异和单侧 PNH。考虑到迄今为止描述的所有 42 个突变的统计分析确定了肌动蛋白结合域中 PNH 的热点区域 (P < 0.05)。
Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).