Mutations

PSEN1 L235P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Genomic Mutation Name (MET1): g.44723T>C
Genomic Mutation Name (NT1): g.61329T>C
dbSNP ID: rs63749835
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: CTG to CCG
Research Models: 1

Findings

This mutation was first reported in a French family, SAL 510, with familial early-onset Alzheimer’s disease. As reported, this family had four affected individuals who met NINCDS-ADRDA criteria for probable or definite AD. The mutation segregated with disease in this family: three affected siblings were heterozygous carriers and two unaffected siblings were not carriers. Age of onset in this family ranged from 29-35 (mean: 32.5 years). Symptoms included progressive memory and language impairment, tonic-clonic seizures, neurological signs (including Babinski), and myoclonus. Disease progression was rapid, with severe dementia within a few years of symptom onset. The clinical picture in this family was notable for the presence of seizures, typically starting in childhood or early adolescence. However, the authors note that the seizures did not always co-occur with dementia and that a second genetic variant predisposing to epilepsy may be responsible (Campion et al., 1996). A later report expanded the data for this family, indicating five affected family members over three generations, with a revised age of onset ranging from 29-39 years (Campion et al., 1999).

The L235P mutation was detected in an individual with AD, but further clinical details, demographic information, and family history were not reported (Rogaeva et al., 2001).

The L235P was also found in a patient of German origin, known as P.54. The patient experienced onset of dementia at age 32. Her mother died at age 34 with an autopsy-confirmed diagnosis of AD. A great-granparent of P.54 was of French ancestry, leading the authors to speculate a possible French founder effect for this mutation given the discovery of the mutation in the French SAL 510 family (Finckh et al., 2005).

Neuropathology

Neuropathology consistent with AD in at least one affected mutation carrier. Post-mortem examination showed a high density of senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Spongiosis was noted in layer 2. Tangles were observed also in the basal nucleus of Meynert, septal and raphe nuclei, and the locus coeruleus (Campion et al., 1996).

Biological Effect

Unknown.

Research Models

This mutation has been introduced into mouse models of disease including the APP751SL/PS1 KI double mutant which also expresses APP with the London (V717I) and Swedish (K670N/M671L) mutations.

In a single transgenic mouse model, the L235P mutation was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic proteins (Yang et al., 2012).

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

References

Research Models Citations

  1. APP751SL/PS1 KI

Paper Citations

  1. . Increased phosphorylation of tau and synaptic protein loss in the aged transgenic mice expressing familiar Alzheimer's disease-linked presenilin 1 mutation. Neurochem Res. 2012 Jan;37(1):15-22. PubMed.
  2. . A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8;7(10):1582-4. PubMed.
  3. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. 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. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuroreport. 1996 Jul 8;7(10):1582-4. PubMed.

Other mutations at this position

View Table