Mutations

PSEN1 L271V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664780 C>G
dbSNP ID: rs63750886
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was detected in a large pedigree (Tas-1) affected by early onset Alzheimer’s disease. The reported pedigree shows 13 affected individuals over three generations in a pattern consistent with autosomal-dominant inheritance. Presenting clinical features were typical of AD, starting with difficulties in activities of daily living followed by progressive deficits in memory, language, and visuo-spatial skills. Severe dementia typically developed over a span of several years. Myoclonus was a late feature, but spastic paraparesis was not observed. The onset of symptoms ranged from 43 years to the early 60s (mean: 49 years). The age at death ranged from 52 to 65 years, with one affected individual still living at 68 years at the time of the report.

DNA from 18 family members, including five affected individuals, was assessed. All affected individuals were mutation carriers, consistent with L271V conferring pathogenicity in this kindred (Kwok et al., 2003).

Neuropathology

Two affected members of the Tas-1 pedigree were examined neuropathologically. One died of pulmonary emboli at the age of 60, the other of bronchopneumonia at age 57. Macroscopically, both brains showed considerable atrophy of the temporal and posterior white matter with enlargement of the lateral ventricles. The locus coeruleus was depigmented in both cases. Microscopically, a large number of plaques were noted in the neocortex (CERAD rating: severe). Many of the plaques were a variant type: large, non-cored plaques without neuritic dystrophy, reminiscent of cotton-wool plaques (Kwok et al., 2003).

Biological Effect

This mutation affects splicing such that exon 8 is more frequently excluded from transcripts. It also results in an amino acid replacement (D257A) at the splice junction of exons 7 and 9. The effects of these alterations are unclear, however, with experiments in cultured cells versus experiments in vitro yielding contradictory results. In Cos-7 cells, when co-expressed with mutant APP carrying the Swedish mutation, the L271V mutation increased levels of secreted Aβ42 compared with wild-type PSEN1 (Kwok et al., 2003). A similar increase in secreted Aβ42 was observed in HEK293 cells co-expressing wild-type APP (751) (Dumanchin et al., 2006); however, no effect on Aβ production was found in neuroblastoma cells expressing the PSEN1 mutant (Morihara et al., 2000). In contrast, an in vitro  assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed abrogation of Aβ40 and Aβ42 production (Sun et al., 2017).

L271 is within a region that undergoes a dramatic conformational change as a result of APP binding (Zhou et al., 2019; Jan 2019 news). The region moves towards the APP β-strand, forming a new α-helix (TM6a) that interacts with residues in PSEN1's second transmembrane domain. 

Last Updated: 10 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. PubMed.
  2. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
  3. . Absence of endoproteolysis but no effects on amyloid beta production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A. Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):85-90. PubMed.
  4. . 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.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Other Citations

  1. Swedish mutation

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. PubMed.

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