A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate
A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate
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DOI：
10.1038/jhg.2017.53
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发表时间：
2017-09-01
影响因子：
3.5
通讯作者：
Saitoh, Shinji
中科院分区：
文献类型：
--
作者：
Kato, Koji;Miya, Fuyuki;Saitoh, Shinji
我们通过全外显子组测序在一名3岁女孩中发现了一种新的NEDD4L基因杂合错义突变（NM_015277: c.2617G b> a; p.Glu873Lys），该女孩表现出严重的整体发育迟缓、婴儿痉挛、腭裂、心室周围结节性异位和多小回畸形。NEDD4L的HECT结构域突变已经在神经发育障碍以及类似的脑畸形患者中报道过。所有报告的NEDD4L HECT结构域突变患者均表现为脑室周围结节性异位，大多数患者有癫痫发作、皮质异常、腭裂和并指畸形。NEDD4L突变患者独特的临床特征可能有助于在临床上将其与其他基因突变患者区分开来，包括FLNA，这是一种众所周知的心室周围结节性异位的致病基因。尽管有报道称NEDD4L的HECT结构域的突变会导致强制表达系统中AKT-mTOR通路的解除，但我们的western blot分析并未显示来自该患者的淋巴母细胞样细胞系（LCLs）中AKT-mTOR活性水平升高。与强迫过表达系统相反，我们患者的LCLs中AKT-mTOR通路的解除似乎是微妙的。
We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G> A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.