Gene mutations in a Han Chinese Alzheimer's disease cohort.

Limin Ma,Jiewen Zhang,Miaomiao Yang,Yingying Shi,Wan Wang,Mingrong Xia,Yuanxing Zhang,Zhixia Ren

doi:10.1002/brb3.1180

Abstract

ObjectiveAlzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort.MethodsDetailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule‐associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next‐generation sequencing on 53 dementia‐associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence.Results PSEN1 p.L226R was found in an early‐onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal‐temporal dementia gene, TANK‐binding kinase 1 (TBK1) with a typical AD phenotype in a late‐onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients.ConclusionsThus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients.

Highlights

Dementia is a progressive neurodegenerative syndrome character‐ ized by cognitive, behavioral, and neuropsychiatric changes that impair social function and activities of daily living (ADLs; Landeiro et al, 2018)
Clinical and genetic crosstalk exists between Alzheimer’s disease (AD) and other neurode‐ generative diseases, such as frontotemporal lobar degeneration (FTLD) and Parkinson’s disease (PD) (Piccoli et al, 2016); for example, AD with FTLD‐like phenotype (Zekanowski et al, 2006) and AD accompanied by myoclonus, seizures, and spastic parapa‐ resis during the disease (Shea et al, 2016)
The presenilin 1 (PSEN1) p.L226R is localized in transmembrane domain 5 exon 7 of PSEN1 protein and corresponds to a conserved amino acid residue in presenilin 2 (PSEN2) (p.L232)

Summary

| INTRODUCTION

Dementia is a progressive neurodegenerative syndrome character‐ ized by cognitive, behavioral, and neuropsychiatric changes that impair social function and activities of daily living (ADLs; Landeiro et al, 2018). According to the age of disease onset, the AD is classified into two types: early‐onset and late‐onset (Giri, Zhang, & Lu, 2016). The three common causative genes associated with AD include the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes (Sutovsky et al, 2018). Some rare frontotemporal lobar degeneration (FTLD) mutations in genes such as progranulin (GRN), C9orf, and microtubule‐associated protein tau (MAPT) have been de‐ scribed in clinical AD cohorts or families with AD clinical pheno‐ types (Piccoli et al, 2016). Two known mutations, a PSEN1 p.L226R (chr14:73659480) mutation in an EOAD family and a PSEN2 p.H169N (chr1:227075798) in a LOAD family, a novel FTLD gene TANK‐binding kinase 1 (TBK1) p.D534H (chr12:64889341) variant with typical AD phenotype in a LOAD family, and two probably benign MAPT variants p.Q230R and p.V48L (chr17:44060859 and chr17:44049233) in two sporadic EOAD patients, and some other insignificant variants were identified (online Supporting Information Table S2)

| MATERIALS AND METHODS

| DISCUSSION