Mutations

PSEN2 S130L

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.3661C>T
Genomic Mutation Name (NT1): g.19999C>T
dbSNP ID: rs63750197
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: TCG to TTG

Findings

This variant has been detected in individuals with Alzheimer's disease; however, it has not been demonstrated to segregate with disease. Although the pathogenicity of this variant is unclear, it was recently classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012). There is strong evidence that the S130L variant is associated with dilated cardiomyopathy in at least two families, although penetrance is not complete (Li et al., 2006).

The S130L variant was first reported in a kindred from northern Italy (FL056). The proband experienced symptom onset, chiefly memory loss, at age 65. The proband had a family history of dementia, with an affected mother, uncle, and grandfather. Onset age was 65 for the mother and uncle, and unknown for the grandfather. In this family the clinical presentation was characterized by a long disease duration, with many years of mild cognitive impairment before the development of bona fide dementia. Segregation with disease could not be determined (Tedde et al., 2003; Sorbi et al., 2002).

This variant was also identified in a patient with apparent late-onset, sporadic Alzheimer's disease. This patient had disease onset at age 81 with progressive memory impairment and spatial disorientation, as well as mood and personality changes. He rapidly developed language deficits, agitation, delusions, hallucinations, agnosia, aphasia, and mild bradykinesia. Two of the proband's siblings were reported to have Parkinson's disease, but were cognitively healthy. Segregation with disease could not be determined (Tomaino et al., 2007). 

The S130L variant was detected in a Turkish individual who developed late-onset AD. His symptoms started at age 77, with depression, progressive memory impairment, and episodes of spatial disorientation. He also developed mild bradykinesia. His mother and maternal uncle were also affected by memory problems. Segregation with disease could not be determined (Lohmann et al., 2012).

The S130L variant was also one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated, early onset Alzheimer’s disease cases and 179 elderly controls free of AD pathology. The variant was detected in one AD case and one control case. The AD patient developed cognitive symptoms at age 61 and died at age 65 with autopsy-confirmed AD. The precise age of the elderly control case was not reported, but postmortem examination showed an absence of AD pathology (Sassi et al., 2014).

Neuropathology

At least one affected mutation carrier had neuropathology consistent with AD at autopsy (Sassi et al., 2014).

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the S130L variant did not affect levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2, indicating the substitution does not alter steady-state endoproteolytic activity.

When co-transfected with APP carrying the Swedish mutation, the S130L mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005).

Calcium signaling was altered in cultured skin fibroblasts from mutation carriers. Specifically, the resting intracellular calcium concentration was elevated (Li et al., 2006).

This variant has been predicted possibly damaging by in silico analysis (Sassi et al., 2014; Lohmann et al., 2012).

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References

Mutations Citations

  1. APP KM670/671NL (Swedish)

Paper Citations

  1. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  3. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.
  4. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  5. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiology of Aging 23 (1S): S312, 2002
  6. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  7. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  8. . 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

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiology of Aging 23 (1S): S312, 2002
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.