Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer’s Disease

Kadmiri, Nadia El; Zaïd, Nabil; Zaid, Younes; Tadevosyan, Artavazd; Hachem, A.; Dubé, Marie‐Pierre; Hamzi, Khalil; Moutawakil, Bouchra El; Nadifi, Sellama

doi:10.1016/j.neuroscience.2014.03.052

Cited by 16 publications

(10 citation statements)

References 21 publications

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“…Novel frameshift mutations were recently detected in exons 16 and 17 of the APP gene in a cohort of sporadic and familial Moroccan AD patients with strong correlation with clinical symptoms in the early–onset familial cases [81]. Novel frameshift mutations were similarly reported in the PSEN1 and PSEN2 genes in this cohort [82]. In a study of a large South African Xhosa family with early onset AD affecting 12 individuals across 4 generations, a novel Ile143Met (ATT to ATG at nucleotide 677) PSEN1 mutation was found and associated with profound neurofibrillary pathology [83].…”

Section: Perspectives On What Is Knownmentioning

confidence: 62%

Neurogenomics in Africa: Perspectives, progress, possibilities and priorities

Akinyemi

Owolabi

Oyeniyi

et al. 2016

Journal of the Neurological Sciences

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The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.

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Section: Perspectives On What Is Knownmentioning

confidence: 62%

Neurogenomics in Africa: Perspectives, progress, possibilities and priorities

Akinyemi

Owolabi

Oyeniyi

et al. 2016

Journal of the Neurological Sciences

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“…The first novel variant, PSEN1 p.H21Profs*2, is a frameshift mutation resulting in a premature stop codon in the sequences of exon 3, and as a consequence, a truncated protein. Frameshift deletions in PSEN1 and PSEN2 were reported as a possible genetic cause of EOAD; however, the pathogenicity is debatable (El Kadmiri et al, 2014;Jayadev et al, 2010;Perrone et al, 2018). Variable phenotypes of the frameshift deletion mutation carriers including AD, mild cognitive impairment, FTD, and amyotrophic lateral sclerosis have been reported.…”

Section: Discussionmentioning

confidence: 99%

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Wong

Seelaar

Melhem

et al. 2020

Neurobiology of Aging

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Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's diseaseecausing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

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“…If we consider that the Alzheimer Disease & Frontotemporal Dementia Mutation Database lists 26 different A␤PP mutations discovered for AD (10 complete gene duplications and 16 missense mutations) from tens of separate publications, the likelihood that so many novel, unprecedented fAD mutations in A␤PP would be discovered in one study is infinitesimally small. In their second paper [122] Kadmiri et al claim to have found frameshift mutations in exon 10 of PSEN1 (Fig. 1C) and in exons 5 and 9 of PSEN2 (Fig.…”

Section: Real and Artefactual Exceptions To The "Fad Mutation Readingmentioning

confidence: 90%

“…The position of the unique frame-shift fAD mutation K115Efs and of the S130L mutation causing Dilated Cardiomyopathy are highlighted with yellow background. The "mutations" putatively identified by Kadmiri et al [121,122] production of A␤ that could not be inhibited with the ␥-secretase inhibitor L-685,458. However, the activity could be inhibited with the general aspartyl protease inhibitor pepstatin A.…”

Section: Are Presenilins the Only ␥-Secretases?mentioning

confidence: 99%

“…In 2014, Kadmiri et al published two papers reporting the discovery of frameshift mutations in Moroccan fAD families [121,122]. In both papers it is claimed that 17 sporadic cases of AD and eight families with AD were examined, so presumably the same patient cohort forms the basis for both studies.…”

Section: Real and Artefactual Exceptions To The "Fad Mutation Readingmentioning

confidence: 99%

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Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Jayne

Newman

Verdile

et al. 2016

JAD

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Abstract. The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESE-NILIN (PSEN) proteins is in ␥-secretase enzyme activity. One substrate of ␥-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A␤PP/APP) that is a fAD mutation locus. A␤PP is the source of the amyloid-␤ (A␤) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on ␥-secretase activity and A␤ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on ␥-secretase in AD. We then discuss the main ideas regarding the role of ␥-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and A␤PP) and look at alternative roles for A␤PP and A␤ in fAD. We present a case for an alternative interpretation of published data on the role of ␥-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN

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Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer’s Disease

Cited by 16 publications

References 21 publications

Neurogenomics in Africa: Perspectives, progress, possibilities and priorities

Neurogenomics in Africa: Perspectives, progress, possibilities and priorities

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

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