Probable Novel PSEN1 Gln222Leu Mutation in a Chinese Family with Early-Onset Alzheimer's Disease

Author(s): Huayuan Wang, Ruihua Sun, Yingying Shi, Mingrong Xia, Jing Zhao, Miaomiao Yang, Limin Ma, Yajing Sun, Gai Li, Haohan Zhang, Weiwei Qin, Jiewen Zhang*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 8 , 2019

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Background:The rate of occurrence of Alzheimer’s disease is increasing around the world. However, there is still no significant breakthrough in the study of its etiology and pathogenesis.

Objective:To screen Alzheimer's disease pathogenic genes, which may be conducive to the elucidation of the pathogenic mechanisms of Alzheimer's disease And predict the pathogenicity by various computer software.

Method:Clinical and neuroimaging examination, Whole Exome Sequencing, and Sanger sequencing were performed in the proband. Mutation sites were verified in 158 subjects.

Results:We reported a proband carrying a probably novel pathogenic mutation, which clinically manifests as progressive memory loss, visual-spatial disorders, apraxia, psychobehavioral disorders, and temperamental and personality changes. Whole Exome Sequencing detected a novel missense mutation at codon 222 (Q222L), which is a heterozygous A to T point mutation at position 665 (c.665A>T) in exon 5 of the presenilin 1 leading to a glutamine-to-leucine substitution. The mutation was also identified by Sanger sequencing in one family member; nevertheless, it was not detected in the other 7 unaffected family members, 50 sporadic Alzheimer's disease patients and 100 control subjects.

Conclusion:A novel mutation in exon 5 of the presenilin 1 gene (Gln222Leu) in a Chinese family with early-onset Alzheimer’s disease has been reported, besides, it was predicted that the missense mutation was probably a novel pathogenic mutation that was reported for the first time in a Chinese family with early-onset Alzheimer’s disease.

Keywords: Early-onset Alzheimer's disease, familial, mutation, PSEN1 Gln222Leu mutation, dementia, memory loss.

Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet 388(10043): 505-17. 2016
[] [PMID: 26921134]
Shea YF, Chu LW, Chan AO, Ha J, Li Y. Song YQ. A systematic review of familial Alzheimer's disease: differences in presentation of clinical features among three mutated genes and potential ethnic differences 115: 67-75 2016
[PMID: 26337232]
Wu L, Rosa-Neto P, Hsiung GY, Sadovnick AD, Masellis M, Black SE, et al. Early-onset familial Alzheimer’s disease. Can J Neurol Sci 39: 436-45. 2012
[PMID: 22728850]
Somavarapu AK, Kepp KP. Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer’s Disease. J Neurochem 137: 101-11. 2016
[PMID: 26756738]
Gu X, Chu T, Liu L, Han X. Genetic influences on white matter and metabolism abnormal change in Alzheimer’s disease: meta-analysis for neuroimaging research on presenilin 1 mutation. Clin Neurol Neurosurg 177: 47-53. 2019
[] [PMID: 30599314]
Xia M, Chen S, Shi Y, Huang Y, Xu J, Zhao T, et al. Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer’s disease. Neurobiol Aging 36: 3334.e13-. 2015
Lanoiselée H, Nicolas G, Wallon D. Rovelet-Lecrux A3, Lacour M1, Rousseau S, et al.APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases. PLoS Med 14(3)e1002270 2017
[PMID: 28350801]
Zhang M, Elena Yu, He Y. Ability of daily living scale questionnaire and application notesShanghai Psychiatry (Suppl) 5-6 1995
Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutation taster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4): 361-2. 2014
[] [PMID: 24681721]
Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteinsNucleic Acids Res 40(Web Server issue): W452-7 2012
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7): 1073-81. 2009
[] [PMID: 19561590]
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 7(4): 248-9. 2010
[] [PMID: 20354512]
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16): 2745-7. 2015
[] [PMID: 25851949]
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, et al. Screening for PS1 mutations in a referral-based series of AD cases 21 Novel mutations. Neurology 57: 621-5. 2001
[PMID: 11524469]
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 114(4): E476-85. 2017
[PMID: 27930341]
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol 15: 1326-35. 2016
[PMID: 27777022]
Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, et al. Genetic influences on atrophy patterns in familial Alzheimer’s disease: a comparison of APP and PSEN1 mutations. J Alzheimers Dis 35(1): 199-212. 2013
[PMID: 23380992]
Miklossy J, Taddei K, Suva D, Verdile G, Fonte J, Fisher C, et al. Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease. Neurobiol Aging 24(5): 655-62. 2003
[PMID: 12885573]
5xFAD | Alzforum. (n.d.). Retrieved Feb.09, 2019, from
Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al. The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J 31(10): 2261-74. 2012
[PMID: 22505025]
Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, et al. Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease. J Exp Med 212(12): 2003-13. 2015
[PMID: 26481686]
Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ III. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci 33(28): 11606-17. 2013
[] [PMID: 23843529]
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17(5): 1005-13. 1996
[PMID: 8938131]
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, et al. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett 265(1): 61-3. 1999
[PMID: 10327206]

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Article Details

Year: 2019
Published on: 10 October, 2019
Page: [764 - 769]
Pages: 6
DOI: 10.2174/1567205016666190806161342
Price: $65

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