A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report

Abstract

The pathogenesis of Alzheimer's disease is complex, and early-onset Alzheimer's disease (EOAD) is mostly influenced by genetic factors. Presenilin-1, presenilin-2 (PSEN2), and amyloid precursor protein are currently known as the three main causative genes for autosomal dominant EOAD, with the PSEN2 mutation being the rarest. In this study, we reported a 56-year-old Chinese Han proband who presented with prominent progressive amnesia, aphasia, executive function impairment, and depression 5 years ago. The 3-year follow-up showed that the patient experienced progressive brain atrophy displayed on magnetic resonance imaging (MRI) and dramatic cognitive decline assessed by neuropsychological evaluation. This patient was clinically diagnosed as EOAD based on established criteria. A heterozygous variant (NM_000447.2: c.1106T>C) of PSEN2 was identified for the first time in this patient and her two daughters. This mutation causing a novel missense mutation (p.Phe369Ser) in transmembrane domain 7 encoded by exon 11 had not been reported previously in 1000Genomes, ExAC, or ClinVar databases. This mutation was predicted by four in silico prediction programs, which all strongly suggested that it was damaging. Our results suggest that this novel PSEN2 Phe369Ser mutation may alter PSEN2 protein function and associate with EOAD.

Identifying novel compounds against the mutational impact on the PSEN2 protein via molecular docking studies.

“…This stimulates the urge to discover more effective treatments and raises a need to speeden up AD research (Association & Alzheimer's Association, 2019). Development of high end sequencing methods has made a drastic progress in sequencing of diseased genomes and identification of novel mutations that are associated with diseases leading to advancements in clinical research (Phillips et al, 2014) .Novel Mutations associated with Alzheimer's disease are being identified now and then (Wan et al, 2021). Till date, around 60 mutations of PSEN2 protein have been identified and mentioned in literature (Hsu et al, 2018).…”

“…There is a lack of information on the characterization of the missense mutations that are associated with familial AD. Though novel mutations are being identified, the pathophysiological mechanism of AD (Wan et al, 2021) , effects of mutations associated with the genes APP, PSEN1 and PSEN2 which are linked to the autosomal dominant familial forms of AD are unknown. With an increasing number of AD cases every year, the quest for a clear picture on this information by considering active research on AD as a priority is inevitable.…”

Identifying Novel Compound against the Mutational Impact on the Mapt Protein via Molecular Docking Studies

“…As the world's population ages, this number is predicted to more than triple, approaching 115 million by 2050 (Sinha, 2011;Wortmann, 2012).The introduction of high sequencing technology has resulted in significant progress in the sequencing of diseased genomes and the identification of novel mutations linked to diseases, resulting in advances in clinical research (Phillips et al, 2014). Every now and then, new mutations linked to Alzheimer's disease are discovered (Wan et al, 2021).The three single-gene mutations associated with early-onset Alzheimer's disease are:(i)Amyloid precursor protein (APP) on chromosome 21 (ii)Presenilin 1 (PSEN1) on chromosome 14 (iii)Presenilin 2 (PSEN2) on chromosome 1 (Rose, 1998). To date nearly 40 mutations associated with MAPT protein.…”