The novel I213S mutation in PSEN1 gene is located in a hotspot codon associated with familial early-onset Alzheimer's disease

Mutations in presenilin 1 gene ( PSEN1 ) are the most common causes of autosomal dominant early-onset Alzheimer's disease (EOAD). We report a novel PSEN1 mutation (I213S) that was discovered in an Italian patient with a family history of early-onset dementia, who developed a slowly progressive cognitive decline since the age of 40 years. Clinical investigations, including neuropsychological assessment, brain MRI and 18-fluorodeoxyglucose PET, as well as cerebrospinal fluid biomarkers, supported the diagnosis of EOAD. Genetic studies identified a novel missense mutation at codon 213 (I213S). Three other mutations at the same codon have been described in association with EOAD. Previous in silico , in vitro and in vivo studies indicated that these mutations affect the functional properties of gamma -secretase and are most likely pathogenic. In silico algorithms suggested that even the I213S mutation has similar deleterious effects on PSEN1 structure and function. Overall, these data strongly support a role of hotspot site for the codon 213 of PSEN1, and provide evidence that the genetic variants located on this site cause EOAD. (C) 2022 The Author(s). Published by Elsevier Inc.

Automated summary

Mutations in the PSEN1 gene are common causes of early-onset Alzheimer's disease. We report a novel PSEN1 mutation (I213S) found in an Italian patient with a family history of early-onset dementia. The patient experienced a gradual cognitive decline starting from the age of 40. Clinical and genetic studies suggest that this mutation may contribute to EOAD.