关键词: ALADIN NDC1 achalasia alacrima neurodevelopmental disorder nuclear pore complex peripheral neuropathy triple A syndrome

来  源:   DOI:10.1016/j.xhgg.2024.100327

Abstract:
Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.
摘要:
核孔复合物(NPC)调节核质运输,并通过跨膜核孔蛋白NDC1锚定在核膜中。NDC1对于有丝分裂后的NPC组装和ALADIN募集到核包膜至关重要。虽然没有人类疾病与三种跨膜核孔蛋白之一有关,AAAS中的双等位基因变体,编码ALADIN,导致三A综合征(Allgrove综合征)。三甲综合症,以屈光病为特征,贲门失弛缓症和肾上腺功能不全,通常包括进行性脱髓鞘性多发性神经病和其他神经系统疾病。在这份报告中,对来自4个与AAAS阴性AAA综合征无关的近亲家庭的7名个体进行了诊断外显子组和/或RNA测序.随后进行了分子和临床研究,以阐明致病机制。受影响的人出现智力残疾,运动障碍,严重脱髓鞘伴继发性轴索多发性神经病,屈氏和贲门失弛缓症。.受影响的个体没有肾上腺功能不全。所有出现双等位基因NDC1框内缺失或错义变异的个体,影响ALADIN结合所需的氨基酸和蛋白质结构域。没有报道与表型特征相关的其他显著变异。来自受影响个体的皮肤成纤维细胞显示ALADIN向NE的募集减少,有丝分裂后的NPC插入减少,确认变体的致病性。一起来看,我们的结果提示双等位基因NDC1变异在多发性神经病和无肾上腺功能不全的三A样疾病的发病机制中,通过干扰生理NDC1功能,包括招募阿拉丁加入全国人大。
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