Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease.

Chang-He Shi,Dan-Dan Shang,Jing Yang,Jun Wu,Lu Zhao,Shu-Yu Zhang,Yan Ji,Yao Zhang,Yu-Ming Xu,Yu-Sheng Li,Zhi-Hua Yang

doi:10.14336/ad.2018.1109

Chang-He Shi, Dan-Dan Shang + Show 9 more

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https://doi.org/10.14336/ad.2018.1109

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Abstract

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) mutations are responsible for autosomal dominant early-onset Alzheimer’s disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1, PSEN2, and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer’s disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and has a high incidence rate among the elderly people [1]
EOAD cases with presenilin 1 (PSEN1) mutations usually occur at 40–60 years of age, but several PSEN1 mutations have been reported to be associated with very early-onset AD [14]
Each patient was assessed via a series of neuropsychological scales, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinic al Dementia Rating (CDR), and Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and has a high incidence rate among the elderly people [1]. AD can be categorized into early-onset Alzheimer’s disease (EOAD, 65 years of age). There are several de novo EOAD mutations detected in very early-onset sporadic cases of AD [5,6,7,8,9,10]. The PSEN1 gene (NM_000021.3) contains 10 coding exons and three noncoding exons It encodes the PSEN1 protein, which consists of nine transmembrane (TM) domains and a hydrophilic loop (HL) region [11]. EOAD cases with PSEN1 mutations usually occur at 40–60 years of age, but several PSEN1 mutations have been reported to be associated with very early-onset AD (vEOAD;

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