Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy

Li, Xuying; Cui, Yue; Jing, Donglai; Xie, Kexin; Zhong, Xiao-Ling; Kong, Yu; Wang, Yuting; Chu, Min Kyung; Wang, Chaodong; Wu, Liyong

doi:10.1097/wad.0000000000000438

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…As it is easier to find causative mutations in FALS, whole-exome sequencing (WES) was performed in all the 16 FALS cases whose DNA samples were available. The WES was performed as the methods described previously [ 33 ]. Briefly, whole blood-derived DNA was captured to generate a sequencing library using the Agilent SureSelect Human All Exon V6 Kit (Agilent Technologies, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

Huang

et al. 2022

BMC Med Genomics

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Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese. Methods Whole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed. Results WES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p < 0.0001) and 65 age-matched and neurologically normal individuals (0/65) (p < 0.0001). The A382T and G298S mutations were prevalent in Europeans and Eastern Asians, respectively. Additionally, carriers for the M337V mutation are dominated by bulbar onset with a long survival, whereas those for G298S are dominated by limb onset with a short survival. Conclusions Some prevalent TARDBP mutations are distributed in a geographic pattern and related to clinical profiles. TARDBP G298S mutation is a founder mutation in the Southern Chinese ALS population.

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Section: Methodsmentioning

confidence: 99%

Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

Huang

et al. 2022

BMC Med Genomics

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“…Li et al reported another Chinese early-onset AD patient harboring the PSEN2 M239T in 2021. He presented with visuospatial and memory impairment [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort

Dong

Liu

Sha

et al. 2022

JAD

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Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ 42 and Aβ 42/Aβ 40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ 42, Aβ 40 levels, or Aβ 42/Aβ 40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

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Perspectives and a Systematic Scoping Review on Longitudinal Profiles of Posterior Cortical Atrophy Syndrome

Pelak

Mahmood

Abe-Ridgway

2022

Curr Neurol Neurosci Rep

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Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy

Abstract: Supplemental Digital Content is available in the text.

Cited by 4 publications

References 33 publications

Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort

Perspectives and a Systematic Scoping Review on Longitudinal Profiles of Posterior Cortical Atrophy Syndrome

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