Mutations

PSEN1 M146L (A>T)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640371 A>T
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a South American pedigree from Argentina spanning five generations and including more than 110 individuals (Mangone et al., 1995; Morelli et al., 1998). Prominent features included mood changes, early language impairment, myoclonus, seizures, and cerebellar alterations. The mean age at onset was 39 years of age, but significant differences in this age were observed, especially between generations. Co-segregation with disease was established, with three affected individuals found to be carriers of the mutation, and one unaffected individual, 17 years beyond the mean age at onset, determined to be a non-carrier. The variant was also reported in a Brazilian cohort (Takada et al., 2017; Llibre-Guerra et al., 2020)

The most frequent alteration resulting in the M146L mutation appears to be an A>C transversion, M146L (A>C), but as exemplified by these cases, an A>T transversion is also possible. Both transversions are absent from the gnomAD variant database (v2.1.1, January 2022).

Neuropathology
Neuropathology is consistent with AD. In addition, SPECT imaging revealed bilateral frontal, temporo-parietal, and cerebellar hypoperfusion in early stage patients, and in an asymptomatic individual at risk. 

In one carrier of the substitution (nucleotide change unspecified), diffuse plaques were identified as the most prevalent type of Aβ deposit, mostly found in intermediate cortical layers (Maarouf et al., 2008). Also, frequent mature cored neuritic plaques were identified, especially in lower cortical layers. Aβ40 was abundant in the cortex, with the Aβ42/Aβ40 ratio being less than one. Moreover, while levels of the Notch-1 intracellular domain (NICD) were low, levels of N-Cadherin/CTF2 were elevated. Moderate amyloid angiopathy was reported in leptomeningeal vessels.

Also, another carrier of the M146L substitution whose nucleotide change was unspecified, was reported to have Lewy body pathology, as assessed by α-synuclein staining, in the amygdala, cingulate gyrus, and substantia nigra (Leverenz et al., 2020).

Biological Effect
The summary below focuses on the M146L substitution, regardless of its underlying nucleotide change which, in some cases, is not reported.

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

Consistent with these findings, earlier studies in vitro showed the M146L mutation increases Aβ42 and Aβ40 levels, as well as the Aβ42/Aβ40 and Aβ42/Aβ total ratios (Page et al., 2008; Sato et al., 2003; Shioi et al., 2007; Sun et al., 2017). Also, Aβ42 and the Aβ42/Aβ40 ratio were increased in conditioned media from M146L mutant fibroblasts, iPSC-derived neurons, and Chinese hamster ovary cells (Liu et al., 2014; Schrank et al., 2020; Kakuda et al., 2021). Although one study found no significant changes in Aβ38 and Aβ40 levels (Liu et al., 2014), two reported decreases in both, as well as in Aβ43 levels (Kakuda et al., 2021; Liu et al., 2022). Of note, an analysis of several familial AD mutations revealed a correlation between higher Aβ40/Aβ43 ratios in cells and older onsets of disease in carriers; however, M146L was an outlier, with a high Aβ40/Aβ43 ratio and a relatively early onset of disease (Kakuda et al., 2021). Analyses of the short peptides produced during APP processing provided further insights into this and other alterations.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, M146 closely contacts the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). The residue has been implicated in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022).

The M146L mutation also cleaves the calcium sensor STIM1 more efficiently than wild-type PSEN1 in vitro. This appears to impair calcium influx via STIM1 degradation and reduces spine density in cultured cells (Sep 2016 news; Tong et al., 2016). The mutation has also been reported to enhance gating of the IP3 receptor channel and increase the open probability of the mitochondrial permeability transition pore (Toglia and Ullah, 2016). Additionally, iPSC-derived neurons were found to release elevated levels of calcium from the endoplasmic reticulum in response to ryanodine receptor stimulation, a response that was normalized by incubation with dantrolene, a negative allosteric modulator (Schrank et al., 2020). 

Moreover, another study of iPSC-derived neurons, revealed a severe repression of genes involved in the determination of neuronal lineage and synaptic function, with a reactivation of REST, a neural repressor that regulates neuronal differentiation (Caldwell et al., 2020) and which has been implicated in neurodegenerative disease (Hwang and Zukin, 2018). Corresponding changes in histone methylation and chromatin topology were reported.

As examined in patient-derived skin fibroblasts, M146L may also affect signaling pathways related to cellular stress, lysosomal function, and autophagy, as well as tau phosphorylation in non-neural cells (Lopez-Toledo et al., 2022).

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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M146L (A>T): Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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-S

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. M146L (A>T): At least one family with >=3 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: 03 Apr 2023

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References

Mutations Citations

  1. PSEN1 M146L (A>C)

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor

Paper Citations

  1. Mangone CA, Castaño EM, Levy E, Abiusi G, Wisniewski T, Marques MR, Faccio E, Gorelick PB, Frangione B, Sica RE. Early onset Alzheimer's disease in a South American pedigree from Argentina. Acta Neurol Scand. 1995 Jan;91(1):6-13. PubMed.
  2. Morelli L, Prat MI, Levy E, Mangone CA, Castaño EM. Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina. Clin Genet. 1998 Jun;53(6):469-73. PubMed.
  3. Takada LT, Brucki SM, Rodriguez RD, Smid J, Bahia VS, Chadi G, Nitrini R. Autosomal Dominant Early-Onset Alzheimer's Disease: Characterization of a Brazilian Cohort . Alzheimer's & Dementia, July 2017
  4. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
  5. Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
  6. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  7. 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.
  8. Page RM, Baumann K, Tomioka M, Pérez-Revuelta BI, Fukumori A, Jacobsen H, Flohr A, Luebbers T, Ozmen L, Steiner H, Haass C. Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem. 2008 Jan 11;283(2):677-83. PubMed.
  9. Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y. Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem. 2003 Jul 4;278(27):24294-301. PubMed.
  10. Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.
  11. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  12. Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F, Tanzi RE, Koo EH, Ringman JM, Goldstein LS, Wagner SL, Yuan SH. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. PubMed.
  13. Schrank S, McDaid J, Briggs CA, Mustaly-Kalimi S, Brinks D, Houcek A, Singer O, Bottero V, Marr RA, Stutzmann GE. Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology. Int J Mol Sci. 2020 Feb 4;21(3) PubMed.
  14. Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. 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. Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.
  17. Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
  18. Toglia P, Ullah G. The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore. Cell Calcium. 2016 Jul;60(1):13-24. Epub 2016 May 7 PubMed.
  19. Caldwell AB, Liu Q, Schroth GP, Galasko DR, Yuan SH, Wagner SL, Subramaniam S. Dedifferentiation and neuronal repression define familial Alzheimer's disease. Sci Adv. 2020 Nov;6(46) Print 2020 Nov PubMed.
  20. Hwang JY, Zukin RS. REST, a master transcriptional regulator in neurodegenerative disease. Curr Opin Neurobiol. 2018 Feb;48:193-200. Epub 2018 Jan 30 PubMed.
  21. Lopez-Toledo G, Silva-Lucero MD, Herrera-Díaz J, García DE, Arias-Montaño JA, Cardenas-Aguayo MD. Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer's Disease Pathology, Constitute a Potential Object for Early Diagnosis. Front Aging Neurosci. 2022;14:921573. Epub 2022 Jul 1 PubMed.
  22. 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.

Further Reading

Papers

  1. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. Elsworthy RJ, Crowe JA, King MC, Dunleavy C, Fisher E, Ludlam A, Parri HR, Hill EJ, Aldred S. The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons. Transl Psychiatry. 2022 Jul 18;12(1):285. PubMed.
  3. Course MM, Gudsnuk K, Keene CD, Bird TD, Jayadev S, Valdmanis PN. Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain. 2023 Feb 13;146(2):507-518. PubMed.

Protein Diagram

Primary Papers

  1. Mangone CA, Castaño EM, Levy E, Abiusi G, Wisniewski T, Marques MR, Faccio E, Gorelick PB, Frangione B, Sica RE. Early onset Alzheimer's disease in a South American pedigree from Argentina. Acta Neurol Scand. 1995 Jan;91(1):6-13. PubMed.
  2. Morelli L, Prat MI, Levy E, Mangone CA, Castaño EM. Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina. Clin Genet. 1998 Jun;53(6):469-73. PubMed.

Other mutations at this position

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