Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.7073G>A
Genomic Mutation Name (NT1): g.23408G>A
dbSNP ID: rs63749884
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: ATG to ATA


M239I was the third missense mutation in PSEN2 to be associated with Alzheimer's disease. It was identified in an Italian kindred with four reported affected members across two generations. Six siblings participated in the study (three affected and three unaffected at the time of the study). All of the affected individuals were found to carry the M139I mutation; two of the unaffected siblings were also found to be carriers, but symptom-free at ages 58 and 68. In this family, the disease phenotype was quite variable, with a variable age of onset (44-58, and likely later) and variable symptoms, including seizures, myoclonic jerks, severe rigidity in the arms and legs, global cognitive deficits, and impairments in language and attention (Finckh et al., 2000).


Autopsy of one family member confirmed the clinical diagnosis of AD.  Diffuse moderate cortical atrophy was observed without lacunar or large infarcts. Numerous neurofibrillary tangles and senile plaques were observed, the latter most concentrated in the amygdala and less frequent in the hippocampus (Finckh et al., 2000).

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the M239I mutation did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. When cotransfected with APP carrying the Swedish mutation, the M239I mutation produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005). The M239I mutation also was found to alter intracellular calcium homeostasis; specifically, it reduced calcium release in human fibroblasts and cell lines stably or transiently expressing the mutation (Zatti et al., 2004; Zatti et al., 2006).


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Paper Citations

  1. . Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000 May 23;54(10):2006-8. PubMed.
  2. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
  3. . The presenilin 2 M239I mutation associated with familial Alzheimer's disease reduces Ca2+ release from intracellular stores. Neurobiol Dis. 2004 Mar;15(2):269-78. PubMed.
  4. . Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium. 2006 Jun;39(6):539-50. PubMed.

Further Reading

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Primary Papers

  1. . Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000 May 23;54(10):2006-8. PubMed.

Other mutations at this position

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