Mutations

PSEN1 L392V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
dbSNP ID: rs63751416
Coding/Non-Coding: Coding
Genomic Region: Exon 11
Mutation Type: Point, Missense
Codon Change: CTG to GTG

Findings

This mutation was described in conjunction with the cloning of the PSEN1 gene (Rogaev et al., 1995). It was reported as present in members of an Italian pedigree affected by a familial form of early onset AD. Further details about this kindred were not reported.

The L392V mutation was also found in an exceptionally large French kindred, FAD RO1, with at least 36 family members affected by early onset Alzheimer’s (Campion et al., 1995; Campion et al., 1995; Campion et al., 1999). The six-generation pedigree indicates the disease is an autosomal-dominant trait, and genetic analysis confirmed segregation with disease. At least 12 family members met NINCDS-ADRDA criteria for probable AD, and two had autopsy-confirmed AD. In this family, onset ranged from 39 to 52 years of age, with a mean onset of 46 ± 3.5 years and mean age at death of 52.6 ± 5.7 years. Disease in this family was characterized by insidious loss of memory and personality changes, followed by parkinsonism symptoms, including limb rigidity, stooped posture, and bradykinesia. Hallucinations occurred in some affected family members. Myoclonus was frequent, and seizures were an invariable feature of late-stage disease.

Another study found two kindreds carrying the L392V mutation (Raux et al., 2005). The ALZ 147 family had six members affected by early onset familial AD. Onset ranged from 41 to 48 years of age. The ALZ 154 family included five members affected by AD, with onset ranging from 39 to 47 years of age. Further clinical details were not reported.

This mutation was also detected in the proband of a Japanese kindred affected by early onset AD (Ikeuchi et al., 2008). The reported pedigree shows eight affected individuals over three generations. Segregation could not be determined. The proband developed onset at age 39.

In a study of individuals of Spanish descent, this mutation was detected in one out of 176 cases with Alzheimer's disease (Jin et al., 2012). The mutation carrier was described as having familial early onset Alzheimer's disease, with symptoms starting at age 42.5. Further clinical details were not reported.

Neuropathology

At least two mutation carriers met CERAD criteria for definite AD. Postmortem findings showed cortical atrophy, especially in the frontal and temporal lobes, with abundant plaques and neurofibrillary tangles throughout the neocortex and hippocampus. Mild amyloid angiopathy was observed. Lewy bodies were not observed (Campion et al., 1995).

Biological Effect

Expression of mutant presenilin-1 in HEK293 cells increased the Aβ42/Aβ40 ratio in the conditioned media. The mutant protein also had impaired endoproteolysis and resulted in lower levels of NICD, suggesting reduced Notch cleavage by γ-secretase (Ikeuchi et al., 2008).

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References

Paper Citations

  1. . 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.
  2. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  3. . A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology. 1995 Jan;45(1):80-5. PubMed.
  4. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  5. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  6. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  7. . Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Japanese Familial Alzheimer's Disease Database

Primary Papers

  1. . A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology. 1995 Jan;45(1):80-5. PubMed.
  2. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  3. . 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.
  4. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.

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