Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637731 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was detected in a family from mainland China with three affected individuals over two generations. Disease in this family was described as a relatively pure amnestic syndrome without atypical motor or behavioral features. The proband developed progressive memory deficits at age 45, with later behavioral changes. Her brother developed similar symptoms beginning at age 51. Their father died with unclassified severe dementia at age 60, with onset around age 50. The mutation appears to segregate with disease in this family; it was present in the proband and her affected brother, but absent in an unaffected family member (Jiao et al., 2014; Deng et al., 2014).

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

Neuropathology

Unknown. Neuroimaging of the two affected siblings showed enlarged ventricles, as well as atrophy in the hippocampus and frontotemporal regions (Deng et al., 2014).

Biological Effect

F105 was identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species (Liu et al., 2021). Consistently, it was found to decrease the Aβ (37 + 38 + 40) / (42 + 43) ratio in mouse embryonic fibroblasts expressing the variant on a PSEN null background and transduced with human APP-C99 (Apr 2022 news; Petit et al., 2022). Based on analyses of multiple PSEN mutants, this ratio was reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity and correlated with AD age at onset. F105C was also reported to cause tau accumulation and disrupt autophagy and the mTORC1 signaling pathway in neurons differentiated from CRISPR-edited human induced pluripotent stem cells (Chong et al., 2022).

This residue is conserved between PSEN1 and PSEN2, and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted the substitution is damaging (Xiao et al., 2021). It had been classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Jiao et al., 2014; Deng et al., 2014) and as likely pathogenic (Xiao et al., 2021) using the ACMG-AMP guidelines.

Research Models

The F105C mutation was knocked in to human induced pluripotent stem cells (iPSCs) generated from urine cells collected from a healthy Chinese woman (Chong et al., 2022). The knockin was created using a piggyBac plasmid and CRISPR technology. The iPSCs were subsequently differentiated into neurons and characterized.

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.

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-M

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. F105C: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 15 Aug 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.
Deng B, Lian Y, Wang X, Zeng F, Jiao B, Wang YR, Liang CR, Liu YH, Bu XL, Yao XQ, Zhu C, Shen L, Zhou HD, Zhang T, Wang YJ. Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family. Neurotox Res. 2014 Oct;26(3):211-5. Epub 2014 Apr 16 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.
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.
Chong CM, Tan Y, Tong J, Ke M, Zhang K, Yan L, Cen X, Lu JH, Chen G, Su H, Qin D. Presenilin-1 F105C mutation leads to tau accumulation in human neurons via the Akt/mTORC1 signaling pathway. Cell Biosci. 2022 Aug 14;12(1):131. 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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 F105C

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