Mutations

PSEN1 A79V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.22921C>T
Genomic Mutation Name (NT1): g.39475C>T
dbSNP ID: rs63749824
Coding/Non-Coding: Coding
Genomic Region: Exon 4
Mutation Type: Point, Missense
Codon Change: GCC to GTC

Findings

This mutation was first identified in three Alzheimer’s disease patients from the Netherlands. The patients (1005, 1061, and 1087) were not known to be related, but genetic markers flanking PSEN1 suggest a relatively recent common ancestor. All three patients met NINCDS-ADRDA criteria for probable AD and had a family history of dementia. The ages at onset were 53, 55, and 58, consistent with early onset AD. The mutation was absent in the 118 control individuals screened (Cruts et al., 1998).

Two years later, the A79V mutation was reported in a German individual with AD, known as patient 1. Like the previously reported Dutch cases, her symptoms began at age 58. The disease course was initially mild, but ultimately culminated in severe dementia more than 10 years after symptom onset. A similar age at onset and a 10-year disease duration were reported for this patient's mother (Finckh et al., 2000).

This mutation does not appear to be associated with a consistent age at onset, however. A fifth family was identified with a later age at onset than observed previously, with greater variability within the family as well (mean age at onset of 69 years; range: 55 to 78 years). The mutation segregated with disease in this family, with the exception of one affected individual who did not carry the mutation and was thought to have sporadic AD (age at onset: 78 years). Of note, CSF Aβ42 and Aβ42/Aβ40 concentrations were found to be very high in a nondemented mutation carrier from this family who took part in a CSF study at the Alzheimer’s Disease Research Center (ADRC) at Washington University (Kauwe et al., 2007).

Three additional AD patients carrying this mutation have been identified (Rogaeva et al., 2001; Miravalle et al., 2002), and more recently the A79V mutation was detected in a screen of 439 families with a history of late-onset AD (onset at age 65 or later). The mutation was found in four of these families, including in one individual from a previously reported family (Kauwe et al., 2007). The sequenced individual from this family had autopsy-confirmed AD and an age of onset of 76 years. A79V was found also in a sporadic AD case (out of 1,806 screened), but not in 1,346 unrelated controls (Cruchaga et al., 2012).

Over all, this mutation is considered to be pathogenic or likely pathogenic for AD, and although initially identified in the context of early onset AD, may also be associated with late-onset AD.

Neuropathology

Unknown, but at least one affected mutation carrier had autopsy-confirmed AD (Cruchaga et al., 2012).

Biological Effect

In HEK-293 cells expressing APP with the Swedish mutation, A79V increased the Aβ42/Aβ40 ratio by  decreasing Aβ40. There was no change in Aβ42 compared to cells expressing wild-type PSEN1 (Kumar-Singh et al., 2006).

In mouse embryonic fibroblasts lacking PSEN1 and PSEN2, expression of PSEN1 with the A79V mutation resulted in increased Aβ42 levels and an increased Aβ42/Aβ40 ratio in conditioned media compared to concentrations produced by cells expressing wild-type PSEN1. Aβ40 levels and total Aβ (combined Aβ40 and Aβ42) levels were not significantly different from wild-type controls (Kauwe et al., 2007).

In silico, this mutation is predicted to be probably damaging by PolyPhen2 (Cruchaga et al., 2012).

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References

Paper Citations

  1. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  2. . High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
  3. . Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007 May;61(5):446-53. PubMed.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  5. . Genetic mutations associated with presenile dementia. Neurobiology of Aging 23 (1S): S322, 2002
  6. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.
  7. . Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006 Jul;27(7):686-95. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.