Mutations

PSEN2 M239I

Overview

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

Findings

M239I was the third missense mutation in PSEN2 to be associated with Alzheimer's disease. Reported first in an Italian family in 2000 (Finckh et al., 2000), it has since been identified in two additional Italian families (Testi et al., 2012; Tremolizzo et al., 2014). No common ancestor has been established. Disease in these families is quite variable, with diverse clinical presentations, including posterior cortical atrophy in one case.

The first reported kindred contains four affected members across two generations. Genetic analysis was completed in six siblings. All three affected siblings were found to carry the M139I mutation, and two of the three unaffected siblings were also found to be carriers, symptom-free at ages 58 and 68. This apparent lack of segregation may be spurious and attributable to the wide age of onset in this family, or a possible reduced penetrance of the mutation. In this family, the disease phenotype was quite variable. Onset age varied from 44 to 58 years, and likely later. Reported clinical features included seizures, myoclonic jerks, severe rigidity in the arms and legs, global cognitive deficits, and impairments in language and attention (Finckh et al., 2000).

The second Italian family included six affected individuals over two generations. The proband experienced symptom onset, notably memory impairment and a dysexecutive syndrome, at age 50. Apathy, decreased speech production, and social withdrawal were also early features. Extrapyramidal signs occurred later, including myoclonic jerks. She met NINCDS-ADRDA criteria for probable Alzheimer’s disease (McKhann et al., 1984). Four previously deceased family members had experienced onset between the ages of 45 and 50, with death following six to 11 years later. The M239I mutation was detected in the proband, but segregation with disease could not be assessed. No mutations were detected in any of the other genes screened: APP (exons 16-17), MAPT (exons, 1, 9-13), PSEN1, and PGRN. The mutation was absent in 492 unrelated individuals (Testi et al., 2012).

In a third family, the M239I mutation was associated with symptoms consistent with posterior cortical atrophy. The proband was a 52-year-old man with a two-year history of depression, concentration difficulties, and severe visuospatial deficits, including the loss of the ability to a read a clock. He also had progressive deficits in writing and performing simple calculations. He had a family history of early onset dementia, with at least four additional family members affected over three generations. The family pedigree was also affected by major psychiatric disorders with psychotic features. None of the proband’s six siblings were affected by dementia symptoms at ages 42 to 64. It is unknown if they are carriers of the M239I, as they declined genetic testing. The proband was negative for mutations in PSEN1, APP (exons 16-17), PGRN, C9ORF72, and MAPT (exons 9-13) (Tremolizzo et al., 2014).

Neuropathology

Autopsy of one individual in the first kindred identified 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). MRI in the patient with posterior cortical atrophy showed atrophy in the parieto-temporo-occipital regions. FDG-PET showed significant bilateral parietal hypometabolism with milder right frontotemporal hypometabolism (Tremolizzo et al., 2014).

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 co-transfected with APP bearing 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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References

Mutations Citations

  1. APP KM670/671NL (Swedish)

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. . Autosomal Dominant Alzheimer's Disease with Early Frontal Lobe Involvement Associated with the Met239Ile Mutation of Presenilin 2 Gene. J Alzheimers Dis. 2012 Jan 1;31(1):7-11. PubMed.
  3. . First Report of PSEN2 Mutation Presenting as Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2014 Jul 9; PubMed.
  4. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  5. . 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.
  6. . 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.
  7. . 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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Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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