Mutations

PSEN1 R352C

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73678575 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGC to TGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation was reported in a Han Chinese family with a history of early-onset AD (Jiang et al., 2014). The reported pedigree shows three affected individuals over four generations. Specifically, the mutation was detected in two individuals, one affected and one unaffected at the age of 56. Therefore, the mutation does not currently segregate with disease in this family, although the unaffected mutation carrier may be presymptomatic, as onset in the family ranged from 56 to 62 years of age. Disease in this family is characterized by psychiatric and behavioral symptoms in addition to memory loss. The disease course was quite protracted, ranging from 12 to 22 years after onset.

The allele count and frequency of this variant in the gnomAD database were 12 and 0.0043 percent, respectively, suggesting less than 10 percent penetrance (Koriath et al., 2018). Thus, the authors of this more recent study described the variant as "most likely benign" or causing an "only small increase in risk."

Neuropathology

Unknown. Imaging showed global cerebral atrophy.

Biological Effect

In vitro experiments with isolated proteins revealed that production of Aβ42 and Aβ40 were reduced compared with wildtype PSEN1, but the Aβ42/Aβ40 ratio was similar (Sun et al., 2017).

Last Updated: 05 Jul 2019

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References

Paper Citations

  1. . Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease. Neurobiol Aging. 2015 Mar;36(3):1602.e3-6. Epub 2014 Dec 18 PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease. Neurobiol Aging. 2015 Mar;36(3):1602.e3-6. Epub 2014 Dec 18 PubMed.

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