Mutations

PSEN2 N141I (Volga German)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.3694A>T
Genomic Mutation Name (NT1): g.20032A>T
dbSNP ID: rs63750215
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: AAC to ATC
Research Models: 5

Findings

This was the first pathogenic mutation described in PSEN2; it was discovered in conjunction with the cloning of the gene (Levy-Lahad et al., 1995; Rogaev et al., 1995). It is also the most common PSEN2 mutation worldwide, with more than 11 families identified. The origin of these families has been traced to a region along the Volga River in Russia (Bird et al., 1988).

The clinical features associated with the N141I mutation were recently summarized in a comprehensive reivew of PSEN2 mutations (Jayadev et al., 2010). Clinical data for 101 affected individuals in 11 families was reported. The number of affected individuals per family varied from two to 26. The mean age of onset was 53.7 years (range: 39 to 75 years). The mean age at death was 64.2 years, and the mean disease duration was 10.6 years. In these families, disease onset was characterized by memory problems and/or other cognitive deficits. The disease course tended to be slower than is typical of other familial AD mutations, especially those in PSEN1. Pyramidal signs or parkinsonian symptoms were not common early in the disease. Of the 64 AD patients with detailed medical records, 31 percent had one or more seizures and 33 percent had hallucinations, delusions, or other psychotic features.

Although the clinical penetrance of this mutation is very high (approximately 95 percent), there are a few isolated reports of decreased penetrance in which individuals reached the ninth decade without cognitive decline. One mutation carrier in the "HB family" was cognitively intact at age 80 when he died from cancer. Another presumed N141I carrier from the "H family" was similarly dementia-free when he died at age 89, also from cancer.

On a historical note, Alois Alzheimer’s famous patient, Auguste Deter ("Auguste D."), lived in the same region of Germany as a modern-day family with the N141I mutation. This raised the possibility that she too may have carried this mutation (Yu et al., 2010); however, this was later shown not to be the case (Müller et al., 2011; Rupp et al., 2014).

Neuropathology

In general, postmortem analysis of affected N141I mutation carriers has shown extensive amyloid plaques and neurofibrillary tangles, with 17 of 18 brain samples receiving a Braak score of V or VI and a CERAD plaque score of C, thus fulfilling pathologic criteria for definite Alzheimer’s disease (Braak and Braak, 1991; Mirra et al., 1991). Inclusions of α-synuclein were common in the amygdala (14/18, 78 percent) but much less common in the substantia nigra (7/16, 44 percent) and the neocortex (3/17, 18 percent). TDP-43 pathology was not commonly observed (3/13, 23 percent). Hippocampal sclerosis was similarly rare (3/13, 23 percent). For additional details, see Jayadev et al., 2010.

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the N141I 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 N141I mutation produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005).

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References

Mutations Citations

  1. APP KM670/671NL (Swedish)

Paper Citations

  1. . Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973-7. PubMed.
  2. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
  3. . Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol. 1988 Jan;23(1):25-31. PubMed.
  4. . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.
  5. . The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.
  6. . Alois Alzheimer's case, Auguste D., did not carry the N141I mutation in PSEN2 characteristic of Alzheimer disease in Volga Germans. Arch Neurol. 2011 Sep;68(9):1210-1, author reply 1211. PubMed.
  7. . A presenilin 1 mutation in the first case of Alzheimer's disease: Revisited. Alzheimers Dement. 2014 Aug 14; PubMed.
  8. . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
  9. . The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479-86. PubMed.
  10. . 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.

Further Reading

Papers

  1. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  2. . The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.
  3. . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
  4. . Alois Alzheimer's case, Auguste D., did not carry the N141I mutation in PSEN2 characteristic of Alzheimer disease in Volga Germans. Arch Neurol. 2011 Sep;68(9):1210-1, author reply 1211. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973-7. PubMed.
  2. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.

Other mutations at this position

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