Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation.

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

“…Importantly, even though PSEN1 is the most commonly involved gene, with > 231 mutations reported as pathogenic in the Alzforum database (), this study did not find any PSEN1 mutation in the Thai and Philippine cohorts. Moreover, only three Malaysian patients with AD have been identified to carry a novel mutation, Glu280Lys [70]. As Korea is one of the fastest “aging countries” in the world, the number of AD, including EOAD, patients will rapidly increase [24].…”

“…Two APP mutations have been identified in patients from Thailand [12] and Iran [85]. Recently, a novel PSEN1 mutation was reported in a Malaysian family [70]. Our primary goal was to provide clinicians a list of variants that can be accurately used in genetic counseling.…”

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

“… 12 , 14 , 36 , 48 In PSEN1, several novel mutations have been discovered in Korean, Malaysian, and Chinese EOAD patients, such as His163Pro, Leu232Pro, Leu248Pro, and Glu280Lys. 12 , 23 , 41 , 88 PSEN1 H163R, the most frequently described AD causative mutation among French, German, and Turkish Caucasians, has appeared in Korea and Japan. 22 , 47 , 53 , 69 Additional mutations, such as Leu226Phe, Thr116Ile, Met233Thr (Korea), Ile143Thr, and Arg269His (Japan), were also reported in Korea and Japan.…”

“…The existence of two additional pathogenic mutations at codon 280 (Glu280Gly and Glu280Ala) indicates that Glu280 is an important residue in PSEN1. 88 …”

Doença de Alzheimer de início precoce (DAIP): características neuropatológicas e variantes genéticas associadas.

“…A maior parte da DAIP permanece geneticamente inexplicada, por isso, grandes estudos vêm sendo feitos, a fim de que se chegue a uma causa para o surgimento da maioria dos casos de tal doença. Com o avanço tecnológico, foi possível realizar o sequenciamento de genes em famílias afetadas por DAIP, e foram identificados novos genes candidatos a causadores dessa doença, sendo eles: SORL1 (2,18), TYROBP, NOTCH3 (7), PLD3 (39) e PRNP (46). Um estudo anterior realizado com portadores e não portadores do alelo E4 da APOE, encontrou variantes truncadoras de proteínas e variantes missenses significativamente prejudiciais nos genes SORL1 e TREM2 em, respectivamente, 6,10% e 3,64% dos pacientes com DAIP.…”