Mutations

PSEN1 I168del (TTAdel)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653580-73653582 TTA>---
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: TTA to ---
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This deletion of three nucleotides was detected in an Alzheimer's disease patient from mainland China. The proband developed progressive memory deficits at age 38. Three years later, behavioral symptoms surfaced and she also developed spastic paraparesis. She had a positive family history; her mother died of dementia at age 55 and two older siblings were also affected (onset at ages 44 and 46). The mutation was present in the two affected siblings in addition to the proband, and therefore appears to segregate with disease in this family (Jiao et al., 2014).

A subsequent study also reported this mutation in a 54-year-old Chinese woman whose symptoms began at age 48 (Gao et al., 2019). She suffered from memory loss, executive dysfunction, disorientation, dyscalculia, and impaired visuospatial skills. She also had anxiety, extrapyramidal signs, and cerebellar ataxia. She was homozygous for the APOE3 allele.

A family in the UK was also reported as carrying this mutation (nucleotide change unspecified) with a mean age at onset of 54 years (Ryan et al., 2016). Extrapyramidal signs were identified in one of two family members.

Neuropathology

Unknown.

Biological Effect

This mutation is a deletion of three nucleotides: the second and third base pairs of codon I167 and the first base pair of codon I168, resulting in the in-frame deletion of an isoleucine. In several reports, this mutation is referred to as I167del, but following the HGVS nomenclature guidelines (v. 20.05), we refer to it as I168del, assigning the deletion to the most C-terminal position (3’ rule).

In an in vitro assay with isolated proteins, a PSEN1 mutant protein missing an isoleucine at this position (I167del, nucleotide change unspecified) produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). This mutation is predicted to be damaging by in silico analysis using SIFT and MutationTaster software and definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Jiao et al., 2014, Gao et al., 2019)

Last Updated: 25 Mar 2021

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References

Paper Citations

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.
  2. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  3. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 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. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.

Other mutations at this position

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