Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Genetic Institute, Emek Medical Center, Afula, Israel.
Nat Commun. 2019 Feb 5;10(1):605. doi: 10.1038/s41467-019-08493-7.
Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life.
核包膜病是一组由核包膜蛋白基因突变引起的异质性疾病。影响核层相关多肽 1（LAP1）的突变导致两种不同的肌营养不良和进行性肌张力障碍伴小脑萎缩表型。我们报告了 7 名患者在出生时即出现严重进行性神经功能障碍、双侧白内障、生长迟缓及早期死亡。所有患者均为 TOR1AIP1 基因无义突变的纯合子，导致 LAP1B 和 LAP1C 两种蛋白异构体均缺失。患者来源的成纤维细胞表现出核包膜形态的改变和包含被困细胞质细胞器的大核跨越通道。这些成纤维细胞的细胞运动性也明显减少且效率低下。我们的研究描述了两种主要的人类 LAP1 异构体完全缺失，强调了它们在早期发育和器官发生中的关键作用。因此，LAP1 相关缺陷可能具有广泛的临床表现，具体取决于核包膜中两种异构体在整个生命周期中的可用性。
