Abstract

BackgroundMost dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer’s disease (AD).Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects of such mutations have proven important for understanding the pathogenic processes. Here, we performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.ResultsUsing targeted exome sequencing we have screened all coding exons in eleven known dementia genes (PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, other dementia diagnoses or mild cognitive impairment.We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation, named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion.In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4 was prevalent in this patient group with an allele frequency of 54%.ConclusionsAmong the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart from giving important information to the clinical investigation, the identification of disease mutations can contribute to an increased understanding of disease mechanisms.

Highlights

  • Mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1 and Presenilin 2 (PSEN2)) cause early-onset, dominantly inherited forms of Alzheimer’s disease (AD), whereas mutations in the Microtubule-associated protein tau (MAPT)Pagnon de la Vega et al BMC Genomics (2022) 23:99 gene mainly lead to frontotemporal dementia (FTD)

  • We found three AD patients with two previously identified pathogenic mutations in Presenilin 1 (PSEN1) (Pro264Leu and Met146Val)

  • Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders

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Summary

Introduction

Mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1 and PSEN2) cause early-onset, dominantly inherited forms of Alzheimer’s disease (AD), whereas mutations in the MAPTPagnon de la Vega et al BMC Genomics (2022) 23:99 gene mainly lead to frontotemporal dementia (FTD). Mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1 and PSEN2) cause early-onset, dominantly inherited forms of Alzheimer’s disease (AD), whereas mutations in the MAPT. We have previously identified and characterized two different APP mutations, the Swedish mutation [3] and the Arctic mutation [4] Functional analyses of these mutations have significantly increased our understanding of the disease pathogenesis. Whereas the Swedish mutation results in an increased cleavage by β-secretase and thereby elevated levels of all forms of Aβ [5, 6], the Arctic mutation leads to a conformational change of Aβ and increased formation of toxic Aβ protofibrils [7]. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer’s disease (AD). We performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation

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