PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer’s Disease

Abstract

An in depth study of PSEN1 mutation p.Thr116Ile (c.335C>T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. PSEN1 Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer’s disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, in silico predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of PSEN1, which may be critical in PSEN1 functions. An additional pathogenic mutation, PSEN1 Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in PSEN1 activity.

Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing

“…PSEN1 Thr119Ile is located in a conservative HL-I, and a similar pathogenic mutation, Thr116Ile, was found in the same loop. Thus, Thr119Ile may present similar effects as the Thr116Ile mutation 7 . To validate the NGS data, a positive sample was used for screening 35 , in which a novel missense mutation was reported, p.Gly209Ala (c.626 G > C).…”

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

“…This is the first study involving a complex genetic screening among patients with EOAD in Thailand. Currently, only a few studies are available on EOAD in South-East Asia [12,14,16,52,53,54,55]. However, to improve disease diagnosis, genetic screening is important.…”

Potential Fluid Biomarkers for the Diagnosis of Mild Cognitive Impairment

“…Genetic markers may be useful in predicting the conversion of MCI into AD or dementia [56,121,122]. The genetics of MCI remains unclear, however, cognitive abilities and cognitive decline could be heritable [31,117,118,123,124,125,126,127,128,129].…”