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 was detected in a kindred from northern Italy referred to as FL056. The proband experienced symptom onset at age 65, chiefly memory loss. 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. Disease segregation could not be assessed (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 bradikinesia. Two siblings were reported to have Parkinson's disease but no cognitive impairment. Disease segregation could not be assessed (Tomaino et al., 2007). 

This 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 steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared to wild-type PSEN2. When cotransfected with APP carrying the Swedish mutation, the S130L mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). However, this variant has been predicted “possibly damaging” by in silico analysis (Sassi et al., 2014).

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References

Mutations Citations

  1. APP KM670/671NL (Swedish)

Paper Citations

  1. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  2. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiology of Aging 23 (1S): S312, 2002
  3. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  4. . 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.
  5. . 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

Papers

  1. . 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.

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.