A novel PS-1 mutation in an Italian AD family with psychotic symptoms at onset

Introduction. Missense mutations in the Presenilin genes are implicated in the majority of early-onset familial Alzheimer's disease (EOFAD) cases. PS-1 is a multi-spanning membrane protein composed of 467 amino acids, containing 6-9 transmembrane helical domains and a large hydrophilic loop between domains 6 and 7. This region is important from a functional point of view since recent studies have provided evidence that this domain binds with a number of interacting proteins, including glycogen synthase kinase-3β (GSK3β) and its substrate tau, β-catenin and rab11. We have performed a clinical and genetic screening in order to search for additional missense presenilin mutations in families with EOFAD. Materials and Methods. All patients met NINCDS-ADRDA criteria for probable AD of the Department of Neurological Sciences, University of Florence. Genomic DNA from affected individuals and controls was extracted from blood samples using standard techniques. To identify an alteration in the sequence of DNA we used the PCR-SSCP technique followed by DNA sequencing in the presence of aberrant SSCP patterns. Results. We identified an Italian kindred with EOFAD carrying a novel missense mutation in the PS-1 gene. We found the novel disease-causing mutation in two first-degree related patients. The mutation, consisting of a T/C transition in exon 11, leading to a Leu392Pro substitution, is localized in the large hydrophilic loop between transmembrane domains (TM) 6 and 7. Conclusions. We report a novel PS1 mutation associated with a clinical phenotype with memory complaints, extrapyramidal features, myoclonus and generalized seizures, and early age of onset, present in all affected members. For this peculiar phenotype associated with a very common mutation site mutation screening is recommended in all FAD families with atypical features at onset.