Identification and Clinical Analysis of the First Nonsense Mutation in the PSEN1 Gene in a Family With Acute Encephalopathy and Retinitis Pigmentosa.

Chunlin You,Zhihao Lei,Lingna Deng,Xinyi Gao,Victor Wei Zhang,Weike Zeng,Yidong Wang

doi:10.3389/fneur.2020.00319

Abstract

In the present study, we investigated the genetic variation in a family with acute encephalopathy and retinitis pigmentosa. Nine of 25 people in this family underwent genetic testing. Three family members, namely, the proband and the proband's two sisters, showed symptoms resembling those of meningoencephalitis and simultaneously suffered from retinitis pigmentosa. Whole-exome sequencing and Sanger sequencing identified a heterozygous mutation, chr14: 73673106 c.881G>A (p.W294*), in the presenilin 1 (PSEN1) gene in these three family members, and the SWISS-MODEL server predicted the formation of a truncated protein. This mutation was not found in the asymptomatic family members. This mutation is a newly discovered nonsense mutation that results in a truncated protein. Although the current genetic evidences may indicate the likelihood of association, further investigations are needed to establish the genotype and phenotype relationship.

Highlights

The presenilin 1 (PSEN1) gene is located on chromosome 14q24.2 [1], and the encoded presenilin 1 (PS1) protein is widely present in all tissues
In this study, using whole-exome sequencing, we discovered the first nonsense mutation in the PSEN1 gene in a family whose members presented with acute encephalopathy as the prominent symptom and simultaneously suffered from retinitis pigmentosa
All three family members with the PSEN1 mutation presented at a young age with acute encephalopathy as the prominent symptom, characterized by the acute onset of fever, impaired consciousness or mental abnormality, signs of pyramidal tract damage, and meningeal irritation

Summary

Introduction

The presenilin 1 (PSEN1) gene is located on chromosome 14q24.2 [1], and the encoded presenilin 1 (PS1) protein is widely present in all tissues. PSEN1 mutation results in an increase in β-amyloid (mainly Aβ42), which is currently thought to be an important mechanism of the pathogenesis of Alzheimer’s disease [3, 4]. PS1 controls the Notch signaling pathway and mediates other physiological activities, such as regulation of the Wnt/beta-catenin signaling pathway, modulation of phosphatidylinositol. 3-kinase/Akt and MEK/ERK signaling, trafficking of select membrane proteins and/or intracellular vesicles, trafficking and turnover of epidermal growth factor receptor [5], modulation of phospholipase C and protein kinase C signaling [6], and regulation of calcium homeostasis [7, 8]. Animal studies of PSEN1 gene knockout have shown that loss of function can lead to neuronal generation disorders or degenerations, heart failure, longitudinal bone formation disorders [9,10,11], et al. Currently, as many as 309 PSEN1 mutations have been described

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Conclusion