Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Park, Hyun Kyung; Na, Duk L.; Lee, Jae Hong; Kim, Jong-Won; Ki, Chang‐Seok

doi:10.3346/jkms.2008.23.2.213

Cited by 30 publications

(21 citation statements)

References 23 publications

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“…An AO of 58 years had been suggested as a cutoff point for genetic analysis based on Western data 9,23. AO was 31, 35, and 34 years in EOAD subjects with genetic mutation, and 62- and 55-year-old patients with AO did not carry causative mutations in a prior Korean study 28. Similarly, AO was 38, 37, and 54 years in our EOAD patients with causative mutation.…”

Section: Discussionsupporting

confidence: 54%

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A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

An¹,

Park²,

Bagyinszky³

et al. 2016

CIA

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Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16–17), PSEN1 (exons 3–12), and PSEN2 (exons 3–12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population.

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Section: Discussionsupporting

confidence: 54%

“…In 2008, Park et al published a genetic screening study, but they employed only 6 EOAD patients. PSEN1 G206S and M233T and APP V715M causative mutations were found in 3 unrelated patients including 1 without family history 28. In 2010, Kim et al published a study on PSEN1 M139I in a family with EOAD 29.…”

Section: Discussionmentioning

confidence: 99%

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

An¹,

Park²,

Bagyinszky³

et al. 2016

CIA

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“…It was confirmed by Sanger sequencing, which revealed 8 carriers of the p.M233T among family members ( Figure 1a ). This pathogenic mutation was reported in several early onset AD families (Campion, et al, 1999,Guerreiro, et al, 2010, Kwok, et al,1997, Park, et al,2008, Raux, et al, 2005). …”

Section: Resultsmentioning

confidence: 75%

Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Ghani

Lang

Zinman

et al. 2015

Neurobiology of Aging

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Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g. mutation screening). We investigated 192 patients with four different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing including PSEN1 p.M233T responsible for Alzheimer’s disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with Amyotrophic Lateral Sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer’s disease and LRRK2 p.R1514Q in 6 out 98 patients with Parkinson’s Disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.

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“…Previous studies have shown several APP and PSEN1 mutations in Asian populations, but pathogenic PSEN2 mutation has not yet been described [3,4]. We had screened PSEN2 mutation in 90 AD patients of two memory clinics from May to December 2012.…”

Section: Introductionmentioning

confidence: 99%

Probable novel PSEN2 Val214Leu mutation in Alzheimer’s disease supported by structural prediction

et al. 2014

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BackgroundPSEN2 mutations are rare variants, and fewer than 30 different PSEN2 mutations have been found. So far, it has not been reported in Asia.Case presentationPSEN2 mutation at codon 214 for predicting a valine to leucine substitution was found in a 70-year-old woman, who showed a dementia of the Alzheimer type. We did not find the mutation in 614 control chromosomes. We also predicted the structures of presenilin 2 protein with native Val 214 residue and Leu 214 mutation, which revealed significant structural changes in the region.ConclusionIt could be a novel mutation verified with structural prediction in a patient with Alzheimer’s disease.

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Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Cited by 30 publications

References 23 publications

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Probable novel PSEN2 Val214Leu mutation in Alzheimer’s disease supported by structural prediction

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Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Cited by 30 publications

References 23 publications

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer&rsquo;s disease

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer&rsquo;s disease

Mutation analysis of patients with neurodegenerative disorders using NeuroX array

Probable novel PSEN2 Val214Leu mutation in Alzheimer’s disease supported by structural prediction

Contact Info

Product

Resources

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A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease