Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653577 T>G
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation has been identified in several European families and individuals diagnosed with Alzheimer's disease (AD). It was first described as associated with early onset AD in a family of Spanish origin. The reported pedigree contained six affected individuals over three generations. In this family, symptoms became apparent between the ages of 32 and 44. The proband began to experience memory decline at age 32. A neurological exam also showed a grasping reflex and bradykinesia. The proband’s mother was also affected, but her age of onset is unknown. His maternal aunt experienced memory loss at age 44, along with irritability and depression. She also developed aphasia and akinetic movements. The mutation was found to segregate with disease; it was present in the proband but absent in two healthy family members aged 37 and 60. The L166R mutation was also detected in two healthy individuals, who, at age 25 and 28, were below the average age of onset in this family (Ezquerra et al., 2000). This family was included in a later mutation-prevalence study conducted in Spain (Lleó et al., 2002).

This mutation was also identified in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, U.K (Ryan et al., 2016). The age at onset of this carrier was 40, and clinical presentation included behavioral symptoms, spastic paraparesis, and extrapyramidal signs.

In addition, the variant was reported in a Hungarian woman diagnosed with familial AD (P111; Csaban et al., 2022). Her age at onset was 45 years and her symptoms included spastic paraparesis, dysarthria, dysphagia, severe cognitive decline, and progressive loss of speech.

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

Neuropathology

Unknown. MRI of the proband showed cortical atrophy and PET showed parietal hypoperfusion (Ezquerra et al., 2000).

Biological Effect

Two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. Of note, Aβ43, a toxic peptide, was elevated compared to wildtype PSEN1 and to other PSEN1 mutants associated with AD.

Several mutations tied to dementia have been reported at this site. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. L166R: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L166R: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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: 26 Aug 2022

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References

News Citations

Paper Citations

Ezquerra M, Carnero C, Blesa R, Oliva R. A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease. Arch Neurol. 2000 Apr;57(4):485-8. PubMed.
Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. 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.
Csaban D, Illes A, Renata TB, Balicza P, Pentelenyi K, Molnar V, Gezsi A, Grosz Z, Gal A, Kovacs T, Klivenyi P, Molnar MJ. Genetic landscape of early-onset dementia in Hungary. Neurol Sci. 2022 Sep;43(9):5289-5300. Epub 2022 Jun 25 PubMed.
Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 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.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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.

Mutations

PSEN1 L166R

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