rs63749884 — PSEN2 M239I

PSEN2 M239I — A Familial Alzheimer's Mutation with Incomplete Penetrance

Presenilin-2 (PSEN2)¹¹ Presenilin-2 (PSEN2)
Encoded by the PSEN2 gene on chromosome 1q42.13; forms the catalytic aspartyl protease subunit of the gamma-secretase complex alongside presenilin-1, nicastrin, APH-1, and PEN-2 is one of three genes — alongside PSEN1 and APP — in which pathogenic mutations cause familial early-onset Alzheimer's disease (FAD). PSEN2 mutations are the rarest of the three causes (<5% of all early-onset familial cases) and are distinguished from their PSEN1 counterparts by later onset, broader age variability, and documented incomplete penetrance: not every carrier develops the disease.

The M239I mutation (c.717G>A; p.Met239Ile) substitutes methionine for isoleucine at position 239 of the mature PSEN2 protein. It was first described in 2000 in an Italian pedigree with autopsy-confirmed Alzheimer's disease and has subsequently been identified in multiple European families. The same methionine at position 239 is the site of the related M239V mutation (rs28936379), originally discovered in Volga German families in the original 1995 characterization of PSEN2 — making this codon a recognized hotspot for dominant pathogenic substitutions.

The Mechanism

Methionine 239 sits within transmembrane domain 5 of PSEN2, near the active site of the gamma-secretase complex²² gamma-secretase complex
The four-protein complex that cleaves type I transmembrane proteins within the lipid bilayer; its principal substrates relevant to Alzheimer's disease are the amyloid precursor protein (APP) and Notch. In normal APP processing, gamma-secretase cleaves APP to generate a mixture of Aβ peptides, predominantly the shorter Aβ40 form. The M239I substitution alters the geometry of the active-site pore, shifting the cleavage pattern toward production of the longer Aβ42 and Aβ43 peptides — forms that are far more prone to aggregation and amyloid plaque seeding. Published data from the AlzForum mutations database document that M239I produces decreased Aβ40/Aβ42 ratios and altered Aβ(37+38+40)/(42+43) ratios, consistent with this cleavage shift.

Beyond amyloid production, PSEN2 M239I disrupts calcium homeostasis in the endoplasmic reticulum (ER). Zatti et al. 2004³³ Zatti et al. 2004
Patient fibroblasts and engineered HEK293 cells expressing M239I showed significantly reduced Ca2+ release from ER stores compared to controls; capacitative calcium entry was unaffected, indicating specific impairment of store-filling rather than store-refilling. Neurobiol Dis. demonstrated that this ER calcium depletion is a direct consequence of the mutation. A follow-up study confirmed that M239I and related PSEN2 mutations reduce calcium content in both the ER and the Golgi apparatus⁴⁴ both the ER and the Golgi apparatus
This challenges the earlier "calcium overload" model of presenilin pathogenicity; instead, intracellular store depletion may impair neuronal signaling, energy metabolism, and protein processing in ways that promote neurodegeneration independently of amyloid.

Additionally, PSEN2 M239I alters trafficking of cystatin C — a neuroprotective secreted protein — in mouse primary neurons, reducing secretion of its glycosylated form and potentially diminishing the neuroprotective extracellular pool.

The Evidence

The clinical characterization comes primarily from two Italian research groups with access to the original and subsequent pedigrees. Finckh et al. 2000⁵⁵ Finckh et al. 2000
Neurology; Italian family with autopsy-confirmed AD; proband and affected relatives showed onset 44–58 years; two mutation carriers at ages 58 and 68 were cognitively unaffected at the time of examination, providing direct evidence of incomplete penetrance established the key clinical signature of this mutation: onset spanning the fifth and sixth decade, and a demonstrable rate of incomplete penetrance — in the family reported, 5 siblings carried the mutation, 3 developed AD and 2 did not.

A later case report by Testi et al. 2012⁶⁶ Testi et al. 2012
J Alzheimers Dis; characterized a PSEN2 M239I carrier with early frontal lobe hypoperfusion on SPECT imaging; clinical features included severe executive dysfunction, myoclonic tremor, and memory loss — confirming pathogenicity and illustrating the phenotypic heterogeneity, including potential atypical presentations extended the phenotypic picture, confirming the mutation's pathogenicity while documenting atypical presentations including early frontal involvement — a pattern not always seen in sporadic AD.

The key distinguishing feature from PSEN1 mutations is penetrance. PSEN1 mutations produce near-100% penetrance with onset reliably before age 60–65. PSEN2 mutations — including M239I — can skip generations or remain clinically silent past age 70 in some carriers. This creates genuine counseling uncertainty: a confirmed carrier faces substantial but not certain lifetime risk, and the age by which risk substantially accumulates spans four decades.

Practical Actions

For confirmed heterozygous carriers (AG genotype), the primary clinical needs are cognitive monitoring and genetic counseling for the family. Sporadic Alzheimer's prevention trials — including the A4 Study, AHEAD 3-45, and the DIAN-TU program — specifically seek to enroll pre-symptomatic carriers of high-penetrance FAD mutations including PSEN2 variants; enrollment provides access to experimental anti-amyloid interventions (lecanemab, donanemab) currently unavailable outside trials.

The monitoring goal is detecting cognitive change early — specifically mild cognitive impairment (MCI) — because cognitive reserve strategies and trial-based interventions are most effective in the pre-symptomatic or very early symptomatic window. Neurological review every 1–2 years, with neuropsychological testing covering episodic memory, executive function, and language, is appropriate for pre-symptomatic carriers in their 40s and beyond.

Interactions

The most clinically relevant interaction is with APOE genotype. While the Finckh 2000 paper specifically reported no influence of APOE genotype on phenotype in their family, this finding was based on a small pedigree and does not preclude population-level modulation. The APOE ε4 allele (rs429358) accelerates onset and increases severity in sporadic AD and in other FAD mutations; this interaction is plausible but not directly established for PSEN2 M239I specifically.

The homologous mutation at the same codon in PSEN1 — M233V (rs63751287) — produces a far more severe phenotype with onset in the mid-20s and near-100% penetrance, demonstrating how the same amino acid change in the two paralogue subunits of gamma-secretase produces profoundly different clinical trajectories.