Mutations

PSEN1 M146L (A>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Pick's disease
Genomic Mutation Name (MET1): g.25639A>C
Genomic Mutation Name (NT1): g.42193A>C
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to CTG
Research Models: 3

Findings

This pathogenic mutation has been detected in at least fifteen families word-wide. In 2010, haplotype analysis revealed that these kindreds are in fact one extended kindred. A common founder effect was determined to account for the presence of this mutation in over 148 affected individuals dispersed over several centuries and multiple continents. The origin of the mutation was traced to a single family originating from Southern Italy before the 17th century (Bruni et al., 2010).

The M146L mutation was first reported in two families in conjunction with the cloning of the PSEN1 gene in 1995 (Sherrington et al., 1995). The families, known as FAD4 and Tor1.1, had roots in southern Italy and were later shown to share a common ancestor (Bruni, 1998). Age of onset in both families was around 43 years old.

The FAD4 pedigree, also known as the N family, was described prior to the identification of the mutation (Foncin et al., 1985). The family was reported to consist of 43 patients with Alzheimer’s disease. Thirteen were known by history, 21 by medical record, and nine by clinical examination. Five were confirmed histopathologically to have AD. The clinical picture was fairly uniform: the first symptom was memory loss beginning around age 40. Psychotic-like symptoms often followed, then profound dementia, and death around age 50. Akinesia was prominent late feature, often with myoclonus. Grand mal seizures sometimes occurred. A branch of this family, Okla1(FAD4) with three affected individuals over two generations, closely matched what was reported for the family at large with onset at about 43 years (Clark et al., 2005). An additional individual related to this family (p.49) with onset of dementia at 37 years has been reported elsewhere (Finckh et al., 2005).

The Tor1.1 family, from Torino Italy, had a history of early-onset AD. At the time it was first reported in 1991, the pedigree comprised 1500 members, over eight generations. Twenty-two patients with AD were identified, one with a confirmed AD diagnosis by autopsy. The pattern of inheritance was consistent with autosomal dominant transmission. The clinical course in this family was noted to be fairly uniform with a high incidence of myoclonic jerks and epileptic seizures. Psychiatric symptoms such as hallucinations and delusions were frequent later symptoms (Bergamini et al., 1991; Rainero et al., 1994).

Three additional Italian families were reported (Sorbi et al., 1995) and later linked to the Italian kindreds FAD4 and Tor1.1 (Bruni et al., 2010). Two of the families had classical clinical and neuropathological AD, with mean age of onset of 45 ± 3 and 36 ± 3. Death in both families typically followed 4-5 years after onset. The third family had early onset age (35 ± 2 years) but a relatively slow clinical course of disease starting with selective memory impairment for 2-3 years. One member of this family died 18 years after onset. Post-mortem examination confirmed the diagnosis of AD.

A French family carrying this mutation was described and segregation demonstrated. As reported, the family, ALZ 204, had six affected individuals over three generations. Onset ranged from 38-47 years (Campion et al., 1999). This family was later determined to be a branch of the Tor1.1 family (Bruni et al., 1998).

Two patients carrying the mutation were reported (Rogaeva et al., 2001). Clinical details, demographic information, and family history were not included in the publication.

A family with three affected individuals over three generations was described. This family was of Italian and Greek heritage. Two of the affected family members were examined neuropathologically following their deaths at ages at 46 and 48. Disease duration was seven and eight years, with onset at age 39 and 40. Mixed neuropathology was found at autopsy with frequent plaques and tangles (Braak and Braak score of 6) and numerous Pick bodies (Halliday et al., 2005).

Neuropathology

Neuropathology consistent with a diagnosis of AD in multiple affected mutation carriers. Pick bodies have also been noted in some cases (Halliday et al., 2005).

Biological Effect

In vitro, this mutation has been found to increase Aβ42 levels and the Aβ42/Aβ40 and Aβ42/Aβtotal ratios (Page et al., 2008; Sato et al., 2003; Shioi et al., 2007)

Research Models

This mutation has been introduced into several mouse models of disease including the single transgenic PS1(M146L), the double transgenic PS/APP, and the widely used 5xFAD which also carries three APP mutations and the PSEN1 mutation L286V.

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References

Research Models Citations

  1. PS1(M146L)
  2. PS/APP
  3. 5xFAD

Mutations Citations

  1. PSEN1 L286V

Paper Citations

  1. . Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. Neurology. 2010 Mar 9;74(10):798-806. PubMed.
  2. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  3. . Cloning of a gene bearing missense mutations in early onset familial Alzheimer's disease: a Calabrian study. Funct Neurol. 1998 Jul-Sep;13(3):257-61. PubMed.
  4. . [Alzheimer's presenile dementia transmitted in an extended kindred]. Rev Neurol (Paris). 1985;141(3):194-202. PubMed.
  5. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  6. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  7. . Familial Alzheimer's disease. Evidences for clinical and genetic heterogeneity. Acta Neurol (Napoli). 1991 Dec;13(6):534-8. PubMed.
  8. . A new Italian pedigree with early-onset Alzheimer's disease. J Geriatr Psychiatry Neurol. 1994 Jan-Mar;7(1):28-32. PubMed.
  9. . Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439-40. PubMed.
  10. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  11. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  12. . Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.
  13. . Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem. 2008 Jan 11;283(2):677-83. PubMed.
  14. . Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem. 2003 Jul 4;278(27):24294-301. PubMed.
  15. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.

Further Reading

Papers

  1. . Role of TOMM40 rs10524523 Polymorphism in Onset of Alzheimer's Disease Caused by the PSEN1 M146L Mutation. J Alzheimers Dis. 2013 Jan 1;37(2):285-9. PubMed.
  2. . An Alzheimer disease presenilin mutation, syndrome diversity, and a shrinking world. Neurology. 2010 Mar 9;74(10):790-1. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  2. . Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439-40. PubMed.
  3. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):219-22. PubMed.

Other mutations at this position

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