Xintong Zhu, Xiaoyin Tan, Junwen Wang, Limeng Dai, Jia Li, Xingying Guan, Ziyi Wang, Mao Zhang, Jun Hu, Yun Bai, Hong Guo
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引用次数: 0
Abstract
Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.
期刊介绍:
Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.