Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653580_73653582 TTA>---
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: 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 (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.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

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).

A study that examined the full set of Aβ peptides generated by a PSEN1 mutant protein missing an isoleucine at this position (I167del, nucleotide change unspecified) in transfected cells revealed an increase in toxic Aβ43 and a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Importantly, like known pathogenic mutations, this variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples. In an in vitro assay with isolated proteins, this mutant protein (nucleotide change unspecified) produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). However, the latter assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021, Jiao et al., 2014, Gao et al., 2019). Both Jiao and co-workers and Gao and colleagues classified the mutation as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM4-P

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. I168del (TTAdel): Single amino acid deletion.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 08 Nov 2022

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References

News Citations

Paper Citations

Jiao B, Tang B, Liu X, Xu J, Wang Y, Zhou L, Zhang F, Yan X, Zhou Y, Shen L. 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.
Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. 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.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. 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.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
Sun L, Zhou R, Yang G, Shi Y. 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.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.

Mutations

PSEN1 I168del (TTAdel)

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