PDF(Pubmed)
Abstract：
Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.
摘要：
编码核孔复合物（NPC）蛋白的致病基因变体先前与类固醇抗性肾病综合征（SRNS）的发病机理有关。NUP85基因,编码核孔蛋白，与非常罕见的SRNS形式有关，基因型-表型信息有限。我们确定了一个意大利男孩，患有与严重的神经发育障碍相关的SRNS，其特征是小头畸形，轴向低张力,缺乏运动里程碑的成就，和难治性癫痫发作以及脑电图上相关的心律失常模式。脑磁共振成像（MRI）显示call体发育不全和大脑皮层的简化旋转。从3岁开始，这个男孩在我们的小儿肾内科接受了SRNS的随访，肾活检发现局灶性节段肾小球硬化。男孩在SRNS发病32个月后死亡，全外显子组测序分析揭示了NUP85（NM_024844.5）中的一种新的复合杂合变体：611T>A（p。Val204Glu),c.1904T>G（p。Leu635Arg),从父亲和母亲那里继承下来，分别。我们描述了NUP85相关疾病的临床表型，回顾了文献中迄今为止报道的受影响的个体，并且总体上扩展了与这种超罕见遗传条件相关的表型和分子谱。我们的研究表明，作为NUP85相关临床谱的一部分，可能会出现严重的神经系统表型，并强调了核孔蛋白在脑发育过程和神经功能中的重要参与。
