Mutation burden profile in familial Alzheimer's disease cases from India

Adhikarla, Syama; Sen, Somdatta; Kota, Lakshmi Narayanan; Viswanath, Biju; Purushottam, Meera; Varghese, Mathew; Jain, Sanjeev; Panicker, Mitradas M.; Mukherjee, Odity

doi:10.1016/j.neurobiolaging.2017.12.002

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…Both mutations were previously shown to have increased Aβ42 and decreased Aβ40 levels. Moreover, both mutations could elevate the Aβ42/Aβ40 ratio by impairing the gamma secretase functions [49,59,72,[74][75][76].…”

Section: Discussionmentioning

confidence: 99%

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APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Giau

Bagyinszky

Youn

et al. 2019

IJMS

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The number of patients with Alzheimer’s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with EOAD; only three variants were found in Korean patients with EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for EOAD patients can potentially improve our understanding of the molecular mechanisms of AD.

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Section: Discussionmentioning

confidence: 99%

“…Unlike PSEN1 mutations, PSEN2 mutations were a rare in EOAD, with only three variants identified in Korean patients (Table 1). Moreover, the mutation spectrum associated with AD for all Asian countries is shown in Table 2 [29,31,32,[45][46][47][48][49][50][51][52][53].…”

Section: Identified Gene Mutations Of Appmentioning

confidence: 99%

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Giau

Bagyinszky

Youn

et al. 2019

IJMS

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“…VarElect is useful for variant interpretation in genetic disease studies by helping to identify and prioritize associations between variant-containing genes and phenotype keywords. VarElect helped us solve clinical cases in our own laboratory (Alkelai et al 2016(Alkelai et al , 2017Oz-Levi et al 2015;Heimer et al 2016Heimer et al , 2018 and was further used in numerous studies worldwide (Yang et al 2017;Einhorn et al 2017;Ekhilevitch et al 2016;Jia et al 2017;Bafunno et al 2018;Zhang et al 2016;Azim et al 2019;Carneiro et al 2018;Feliubadalo et al 2017;Syama et al 2018). VarElect exploits the GeneCards Suite diverse gene-to-gene relationships to pinpoint the relevance of genes that have no direct association to the phenotype keywords on their own (using the indirect, or "guilt by association" mode).…”

Section: Interpretation Of Single Nucleotide Variants (Snvs)mentioning

confidence: 99%

The GeneCards Suite

Safran

Rosen

Twik

et al. 2021

Practical Guide to Life Science Databases

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The GeneCards® database of human genes was launched in 1997 and has expanded since then to encompass gene-centric, disease-centric, and pathway-centric entities and relationships within the GeneCards Suite, effectively navigating the universe of human biological data—genes, proteins, cells, regulatory elements, biological pathways, and diseases—and the connections among them. The knowledgebase amalgamates information from >150 selected sources related to genes, proteins, ncRNAs, regulatory elements, chemical compounds, drugs, splice variants, SNPs, signaling molecules, differentiation protocols, biological pathways, stem cells, genetic tests, clinical trials, diseases, publications, and more and empowers the suite’s Next Generation Sequencing (NGS), gene set, shared descriptors, and batch query analysis tools.

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“…Second case of Trp165Cys was discovered with alternative codon exchange of TGG > TGT in an Indian family. Affected patients developed disease in their 40s, and disease phenotypes were rapid progressive disease progression and cerebral/cerebellar atrophies [ 37 ]. Our case was associated with probable EOAD case in a male patient, and his family members presented AD in their 40s.…”

Section: Discussionmentioning

confidence: 99%

“… 45–50 Yes Possibly damaging via in silico. [ 19 ] Roeber et al, 2015 W165C (G > C) Not available 37–47 Yes ↑Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio [ 36 ] Campion et al, 1999 W165C (G > T) EOAD, a severe form of atrophies and rapid deterioration in cerebral and cerebellar 45 Yes ↓Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio [ 37 ] Syama et al, 2018 W165G Not available 34–38 Yes Not available [ 39 ] Higuchi et al, 2000 L166H MRI: hippocampal atrophy and cortical atrophy. SPECT: bilateral hypometabolism in the parietal and frontal lobes.…”

Section: Discussionmentioning

confidence: 99%

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

et al. 2019

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Background: Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer's disease (EOAD). Recently, emerging studies reported several novel PSEN1 mutations among Asian. We describe a male with EOAD had a pathogenic PSEN1 mutation. Case presentation: A 53-year-old male presented with memory decline, followed by difficulty in finding ways. Patient had positive family history, since his mother and one of his brother was also affected with dementia. Brain magnetic resonance imaging (MRI) scan showed mild degree of atrophy of bilateral hippocampus and parietal lobe. 18 F-Florbetaben-PET (FBB-PET) revealed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and precuneus. Whole exome analysis revealed a heterozygous, probably pathogenic PSEN1 (c.695G > T, p.W165C) mutation. Interestingly, Trp165Cys mutation is located in trans membrane (TM)-III region, which is conserved between PSEN1/PSEN2. In vitro studies revealed that PSEN1 Trp165Cys could result in disturbances in amyloid metabolism. This prediction was confirmed by structure predictions and previous in vitro studies that the p.Trp165Cys could result in decreased Aβ42/Aβ40 ratios. Conclusion: We report a case of EOAD having a pathogenic PSEN1 (Trp165Cys) confirmed with in silico and in vitro predictions.

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Mutation burden profile in familial Alzheimer's disease cases from India

Cited by 12 publications

References 35 publications

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

The GeneCards Suite

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

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