PSEN2 – Familial Alzheimer's Disease

PSEN2 encodes presenilin 2, a core component of the γ-secretase complex that processes amyloid precursor protein (APP). Heterozygous PSEN2 mutations cause autosomal dominant familial Alzheimer disease (MONDO:0100087) with variable age of onset and full penetrance. Clinical presentation typically includes progressive memory impairment, executive dysfunction, behavioral disturbances, and extrapyramidal signs.

Multiple independent studies have identified five PSEN2 missense mutations—Thr122Pro, Ser130Leu, Ser175Cys, Met239Ile, and Met239Val—in unrelated early-onset Alzheimer families (totaling >20 affected individuals) with clear cosegregation in up to four affected relatives per pedigree (PMID:14623725; PMID:20164579; PMID:22531416; PMID:15055444). Systematic reviews confirm that PSEN2 accounts for ~5% of familial Alzheimer cases worldwide (PMID:26337232). All reported pathogenic variants are missense and cluster within transmembrane domains, suggesting critical structural and catalytic roles.

The prototypical variant c.389C>T (p.Ser130Leu) exemplifies the PSEN2 spectrum (NM_000447.3:c.389C>T (p.Ser130Leu)). No truncating or loss-of-frame mutations have been observed, and no recurrent founder alleles beyond regional clusters have been established. Variants consistently demonstrate autosomal dominant transmission across multi-generational pedigrees.

Functional assays in cell lines and animal models show that PSEN2 FAD mutations increase the Aβ42/Aβ40 ratio by 1.4–2.5-fold, reduce Aβ40 and γ-secretase cleavage of Notch, and exhibit partial loss-of-function in APP and Notch processing (PMID:15663477). Zebrafish models of PSEN2 N140fs truncation reveal viable homozygotes with pigment defects but no early neurodegeneration, highlighting allele-specific mechanistic diversity.

Some PSEN2 variants (e.g., p.Arg62His, p.Arg71Trp) identified in breast cancer cohorts do not alter Aβ42/Aβ40 but impair Notch signaling and presenilin stability, underscoring context-dependent functional effects and the importance of disease-specific interpretation (PMID:16474849).

Integration of robust segregation data, consistent missense variant spectrum, and concordant functional studies supports a definitive gene-disease association for PSEN2 in familial Alzheimer disease. Clinical PSEN2 testing enables early diagnosis, predictive counseling, and selection of patients for γ-secretase–targeted therapies. Key Take-home: PSEN2 missense mutations are causative of autosomal dominant familial Alzheimer disease through gain and partial loss of γ-secretase function and represent actionable biomarkers for diagnosis and therapeutic intervention.

References

• Archives of Neurology • 2003 • Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. PMID:14623725
• Journal of Alzheimer's disease : JAD • 2010 • A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. PMID:20164579
• Journal of Alzheimer's disease : JAD • 2012 • Autosomal dominant Alzheimer's disease with early frontal lobe involvement associated with the Met239Ile mutation of Presenilin 2 gene. PMID:22531416
• Journal of Neuropathology and Experimental Neurology • 2004 • Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. PMID:15055444
• Journal of Neurochemistry • 2005 • Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. PMID:15663477
• Journal of the Formosan Medical Association • 2016 • A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. PMID:26337232
• Oncogene • 2006 • Functional characterization of novel presenilin-2 variants identified in human breast cancers. PMID:16474849

Evidence Based Scoring (AI generated)