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Aging and disease    2019, Vol. 10 Issue (4) : 908-914     DOI: 10.14336/AD.2018.1109
Short Communication |
Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease
Yu-Sheng Li1, Zhi-Hua Yang1, Yao Zhang1, Jing Yang1, Dan-Dan Shang2, Shu-Yu Zhang1, Jun Wu1, Yan Ji1, Lu Zhao1, Chang-He Shi1,*, Yu-Ming Xu1,*
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
2Department of Neurology, Luoyang Central Hospital affiliated to Zhengzhou University, Henan, China
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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.

Keywords Early-onset Alzheimer’s disease      EOAD      Mutation      PSEN1     
Corresponding Authors: Shi Chang-He,Xu Yu-Ming   
About author:

These authors contributed equally to this work.

Just Accepted Date: 23 November 2018   Issue Date: 01 August 2019
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Yu-Sheng Li
Zhi-Hua Yang
Yao Zhang
Jing Yang
Dan-Dan Shang
Shu-Yu Zhang
Jun Wu
Yan Ji
Lu Zhao
Chang-He Shi
Yu-Ming Xu
Cite this article:   
Yu-Sheng Li,Zhi-Hua Yang,Yao Zhang, et al. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease[J]. Aging and disease, 2019, 10(4): 908-914.
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Clinical characteristicsProband in family 1
Proband in family 2
Proband in family 3
(II -2)
Family history++-
Age onset (years)404130
Disease process (years)514
Symptoms onsetMemory declineMemory declineMemory decline
Psychiatric symptoms+++
Extrapyramidal symptoms+--
Cranial MRICerebral cortex and bilateral hippocampal atrophyBilateral frontoparietal lobe demyelinationCerebral cortex and bilateral hippocampal atrophy
Table 1  The clinical characteristics of the proband in the three EOAD families.
PedigreesFamily 1Family 2Family3
Nucleotide Changec.766T>Ac.641A>Gc.641A>G
Amino Acid Changep. Y256NP. H214RP. G206V
LocationExon7, TM-VIExon7, HL-IVExon7, TM-IV
PROVEAN Scores-7.2 (Deleterious)-7.6 (Deleterious)-8.5 (Deleterious)
MutPred2 scores0.953 (Pathogenicity)0.934 (Pathogenicity)0.926 (Pathogenicity)
SNAP scores92 (functional effect)85 ((functional effect)75 (functional effect)
Polyphen 2 scores (HumDiv)1.000 (Probably damaging)1.000 (Probably damaging)1.000 (Probably damaging)
Polyphen 2 scores (HumVar)0.999 (Probably damaging)0.999 (Probably damaging)1.000 (Probably damaging)
MutationTasterDisease causingDisease causingDisease causing
MutationAssessorHigh deleteriousMedium deleteriousMedium deleterious
Table 2  Bioinformatic analyses of PSEN1 variants.
Figure 1.  The pedigree charts and Sanger sequence chromatograms of the three families

A) The pedigree chart of family 1. B) The Sanger sequence chromatogram of family 1. C) The pedigree chart of family 2. D) The Sanger sequence chromatogram of family 2. E) The pedigree chart of family 3. F) The Sanger sequence chromatogram of family 3. Open symbols, unaffected; filled symbols, affected; arrow, proband. Asterisk, members sequenced in the study. Vertical arrows indicate the mutation site.

Figure 2.  The cranial MRI of the probands in the three families

A) The T2 weighed image showed atrophy of cerebral cortex (arrowhead) and hippocampus (arrow) in proband (III-1) in family 1. B) The T2 FLAIR image showed mild white matter demyelination (double arrows) in frontoparietal lobe of the proband (III-2) in family 2. C) The T2 weighed MRI image showed atrophy of cerebral cortex (arrowhead) and hippocampus (arrow) in proband (III-3) of family 3.

Figure 3.  The conservation analysis of the three mutation sites and protein structure modeling of PSEN1

A) conservation analysis of the three mutation sites. Arrow indicates the mutation sites. B) the 3D protein structure modeling wild type and mutation type of PSEN1 protein. The residues in codons 206, 214, and 256 were highlighted. Mutations of Y256N, H214R, and G206V change the residue side chains at the positions 256, 214, and 206 of PSEN1 protein.

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