Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640351 T>A
dbSNP ID: rs63751106
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to AAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was reported in a French woman (ALZ 034) with onset of symptoms at age 37. She met NINCDS-ADRDA criteria for probable AD and died at age 47. This may have been a case of a de novo mutation, as the woman had no family history of dementia. Her parents were unaffected at the age of 74 and neither had a family history of dementia. The mutation was absent in the woman’s mother (age 74) and brother (age 50) (Dumanchin et al., 1998). In a subsequent study, a French individual carrying this mutation with symptom onset at age 37 (most likely the same carrier) was reported as developing seizures at age 42 (Zarea et al. 2016).  The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropathological data are unavailable, but MRI of the proband showed diffuse cortical atrophy and PET/SPECT revealed hypoperfusion of the occipito-temporo-parietal cortices (Lacour et al., 2019).

Biological Effect

The biological effects of this variant are unknown. However, multiple pathogenic mutations at this position have been reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates M139 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. Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PubMed.
2. 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.
3. Lacour M, Quenez O, Rovelet-Lecrux A, Salomon B, Rousseau S, Richard AC, Quillard-Muraine M, Pasquier F, Rollin-Sillaire A, Martinaud O, Zarea A, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Magnin E, Sauvée M, Marelli C, Gabelle A, Pariente J, Paquet C, Boland A, Deleuze JF, Campion D, Hannequin D, Nicolas G, Wallon D, collaborators of the CNR-MAJ. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. 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