Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653577 T>G
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation is associated with early onset Alzheimer’s disease in a family of Spanish origin. The reported pedigree contains 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.

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

Unknown. 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).

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References

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading