Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173643 T>C
Position: (GRCh37/hg19):Chr14:73640351 T>C
dbSNP ID: rs63751106
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 1

Findings

This mutation has been reported in several European families. 

A French family known as CAE 010 was found to carry this mutation and to have a history of early onset Alzheimer’s disease. The proband and one affected first-degree relative were both mutation carriers. They experienced symptom onset at age 48 and 50 (Campion et al., 1995; Campion et al., 1999). In a subsequent study, seizures were reported in one of two French mutation carriers eight years after AD onset (Zarea et al. 2016). 

This mutation was also detected in two Spanish sisters who began to experience cognitive symptoms at ages 47 and 48. Depression and anxiety were also present, with later behavioral disturbances. Both were diagnosed with probable AD. The sisters did not have a family history of dementia; however, their parents had died early, at age 35 and 65, from an accident and cancer, respectively. Neither parent had shown signs of cognitive decline at the time of their death (Queralt et al., 2001).

A second Spanish family with familial AD has been reported (Lleó et al., 2002). The mean age of onset in this family was 45.2 (range: 39 to 51 years). The mean age at death was reported as 54.1 (range: 45 to 64 years). The clinical presentation was noted as fairly typical for AD, and family members met NINCDS-ADRDA criteria (McKhann et al., 1984), but additional clinical details were not reported.

Another individual of Spanish descent was also found to carry this mutation (Jin et al., 2012). This individual was described as having early onset sporadic AD with onset at age 47.5. Further clinical details were not reported.

Follow-up studies have looked for changes in brain and fluid biomarkers in presymptomatic mutation carriers. Although the number of subjects is small, one study showed that preclinical carriers had relatively high levels of Aβ1-42 in the cerebral spinal fluid, suggesting that this mutation may be associated with a relative overproduction of Aβ early in life (Portelius et al., 2012). An imaging study showed that asymptomatic PSEN1 mutation carriers, including those carrying the M139T mutation, had increased cortical thickness in the precuneus and parietotemporal areas and increased caudate volumes approximately 10 years before predicted symptom onset. Although the reasons for this paradoxical increase in brain volume are not clear, one hypothesis postulates reactive neuronal hypertrophy early in the disease process (Fortea et al., 2010).

The variant is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Unknown.

Biological Effect

In vitro, this mutation was associated with an increased Aβ42/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). In membrane samples from three patient brains incubated with tagged APP-C99 substrate, production rates of Aβ38 and Aβ40 were decreased and the Aβ42/Aβ40 ratio was increased compared with control samples (Szaruga et al., 2015). The mutation appears to impair the fourth γ-secretase cleavage in at least one of the Aβ production lines that sequentially digest Aβ into shorter peptides as revealed by a decrease in the Aβ38/Aβ42 (product/substrate) ratio.

More recently, two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed deleterious decreases in both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Petit et al., 2022; Liu et al., 2022; Apr 2022 news). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

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.

Research Models

A rat model carrying this mutation and a humanized Aβ sequence within the rat APP gene has been created (Serneels et al., 2020). These knock-in animals, App^hu/hu;Psen1M139T^+/+, are homozygous for both humanized APP and PSEN1 M139T.

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References

Research Models Citations

1. App knock-in (humanized Aβ) (Leuven); Psen1 knock-in (M139T)

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Serneels L, T'Syen D, Perez-Benito L, Theys T, Holt MG, De Strooper B. Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer's disease. Mol Neurodegener. 2020 Oct 19;15(1):60. PubMed.
2. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
3. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
4. 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.
5. Queralt R, Ezquerra M, Castellví M, Lleó A, Blesa R, Oliva R. Detection of the presenilin 1 gene mutation (M139T) in early-onset familial Alzheimer disease in Spain. Neurosci Lett. 2001 Feb 23;299(3):239-41. PubMed.
6. 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.
7. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
8. Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, Ibero-American Alzheimer Disease Genetics Group Researchers, Cruchaga C. Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
9. Portelius E, Fortea J, Molinuevo JL, Gustavsson MK, Andreasson U, Sanchez-Valle R. The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease. Mol Med Report. 2012 Apr;5(4):1111-5. PubMed.
10. Fortea J, Sala-Llonch R, Bartrés-Faz D, Bosch B, Lladó A, Bargalló N, Molinuevo JL, Sánchez-Valle R. Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis. 2010;22(3):909-22. PubMed.
11. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
12. Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, Ryan NS, Lashley T, Fox NC, Murayama S, Gijsen H, De Strooper B, Chávez-Gutiérrez L. Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
13. 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.
14. 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.
15. 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.
16. 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