Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173574 C>T
Position: (GRCh37/hg19):Chr14:73640282 C>T
dbSNP ID: rs63750730
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first reported in a 48-year-old Italian woman with a three-year history of progressive memory impairment. She did not have a family history of dementia, so the mutation may have arisen de novo; however, it may have been transmitted through the maternal line. The proband’s mother and maternal grandmother died in their 40s from unrelated causes (bone cancer and an accident, respectively), so it is not known whether they would have developed dementia had they lived. The mutation was absent in the patient’s father and in 100 healthy unrelated controls (La Bella et al., 2004).

This mutation was also detected in the proband of a family known as ANG 008, in which four family members were also affected by dementia. This study reported the age of onset as 40 to 47 years. Family members met NINCDS-ADRDA criteria for Alzheimer’s disease, but postmortem confirmation of the diagnosis was not available (Raux et al., 2005). This family was also described in a large French study. The clinical data for five affected family members was summarized as disease onset at age 38 to 44 (younger than previously reported), and duration ranging from three to five years. DNA from family members was not available, therefore segregation with disease could not be determined. In a subsequent study, seizures were reported in two French mutation carriers (Zarea et al. 2016). The average time between AD onset and first seizure was 3.5 years.

The mutation was also found in two Korean families with a strong family history of disease (An et al., 2016; Bagyinszky et al., 2018). One family had an autosomal dominant pattern of AD inheritance including at least 11 affected individuals spanning two generations (An et al., 2016). The proband was a woman diagnosed with probable AD whose initial symptom was memory loss at age 38. She also presented with mood alterations, and marked ideopmotor apraxia.

In the other Korean family, the proband had disease onset at 41 years and symptoms included memory impairment, confusion, visuospatial dysfunction, and speech disturbances (Bagyinszky et al., 2018). The family included four affected members spanning two generations. The mutation was identified in the proband and a sister with mild memory impairment, and was absent from two asymptomatic sisters, as well as from genomic databases including the Korean Reference Genome Database, 1000Genomes, and gnomAD.

Neuropathology

Neuropathological data are unavailable. In one patient, however, MRI showed atrophy in the right temporal and parietal regions, and some vascular abnormality in the left frontal area (Bagyinszky et al., 2018). In another patient, MRI revealed atrophy in the medial region, and FDG-PET showed bilateral hypometabolism in temporal and parietal regions (An et al., 2016).

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels.

Consistent with these findings, several in silico analyses indicate it likely affects PSEN1 function (Bagyinszky et al., 2018, Xiao et al., 2021). Although Bagyinszky and colleagues reported the SIFT algorithm classified it as “tolerated,” they also reported PolyPhen2 predicted it is probably damaging, PROVEAN classified it as deleterious, and ExPasy suggested significant changes in the site’s hydrophobicity, bulkiness, and polarity. Moreover, 3D modeling using Raptor X, indicated the mutation likely disrupts the conformation of PSEN1’s first hydrophilic loop, an evolutionarily conserved domain. The mutation has been classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Wallon et al., 2012).

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.

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References

Paper Citations

1. La Bella V, Liguori M, Cittadella R, Settipani N, Piccoli T, Manna I, Quattrone A, Piccoli F. A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early-onset Alzheimer's disease. Eur J Neurol. 2004 Aug;11(8):521-4. PubMed.
2. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
3. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
4. An SS, Park SA, Bagyinszky E, Bae SO, Kim YJ, Im JY, Park KW, Park KH, Kim EJ, Jeong JH, Kim JH, Han HJ, Choi SH, Kim S. A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. Clin Interv Aging. 2016;11:1817-1822. Epub 2016 Dec 15 PubMed.
5. Bagyinszky E, Lee HM, Van Giau V, Koh SB, Jeong JH, An SS, Kim S. PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer's Disease. Int J Mol Sci. 2018 Sep 2;19(9) PubMed.
6. 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.
7. 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.
8. 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.
9. Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.

External Citations

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Further Reading