Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Pick's disease
Position: (GRCh38/hg38):Chr14:73173663 A>C
Position: (GRCh37/hg19):Chr14:73640371 A>C
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 18

Findings

This pathogenic mutation has been detected in at least 15 families worldwide. In 2010, haplotype analysis revealed that these kindreds were in fact one extended kindred. A common founder effect was determined to account for the presence of this mutation in more than 148 affected individuals dispersed over several centuries and multiple continents. The origin of the mutation was traced to a single family originating from Southern Italy before the 17th century (Bruni et al., 2010; Borrello et al., 2016).

The M146L mutation was first reported in two families in conjunction with the cloning of the PSEN1 gene in 1995 (Sherrington et al., 1995). The families, known as FAD4 and Tor1.1, had roots in southern Italy and were later shown to share a common ancestor (Bruni, 1998). Age of onset in both families was approximately 43 years old.

The FAD4 pedigree, also known as the N family, was described prior to the identification of the mutation (Foncin et al., 1985). The family was reported to consist of 43 patients with Alzheimer’s disease. Thirteen were known by history, 21 by medical record, and nine by clinical examination. Five were confirmed histopathologically to have AD. The clinical picture was fairly uniform: The first symptom was memory loss, beginning around age 40. Psychotic-like symptoms often followed, then profound dementia, and death around age 50. Akinesia was a prominent late feature, often with myoclonus. Grand mal seizures sometimes occurred. A branch of this family, Okla1(FAD4), with three affected individuals over two generations, closely matched what was reported for the family at large, with onset at about 43 years (Clark et al., 2005). An additional individual related to this family (p.49) with onset of dementia at 37 years has been reported elsewhere (Finckh et al., 2005).

The Tor1.1 family, from Torino Italy, had a history of early onset AD. When it was first reported in 1991, the pedigree comprised 1,500 members over eight generations. Twenty-two patients with AD were identified, one with a confirmed AD diagnosis by autopsy. The pattern of inheritance was consistent with autosomal-dominant transmission. The clinical course in this family was noted to be fairly uniform, with a high incidence of myoclonic jerks and epileptic seizures. Psychiatric symptoms such as hallucinations and delusions were frequent later symptoms (Bergamini et al., 1991; Rainero et al., 1994).

Three additional Italian families were reported (Sorbi et al., 1995) and later linked to the Italian kindreds FAD4 and Tor1.1 (Bruni et al., 2010). Two of the families had classical clinical and neuropathological AD, with mean age of onset of 45 ± 3 and 36 ± 3. Death in both families typically followed four to five years after onset. The third family had early onset age (35 ± 2 years) but a relatively slow clinical course of disease, starting with selective memory impairment for two to three years. One member of this family died 18 years after onset. Postmortem examination confirmed the diagnosis of AD.

A French family carrying this mutation was described and segregation demonstrated. As reported, the family, ALZ 204, had six affected individuals over three generations. Onset ranged from 38 to 47 years (Campion et al., 1999). This family was later determined to be a branch of the Tor1.1 family (Bruni et al., 1998).

Two patients carrying the mutation were reported (Rogaeva et al., 2001). Clinical details, demographic information, and family history were not included in the publication.

A family with three affected individuals over three generations was described. This family was of Italian and Greek heritage. Two of the affected members were examined neuropathologically following their deaths at ages at 46 and 48. Disease duration was seven and eight years, with onset at age 39 and 40. Mixed neuropathology was found at autopsy with frequent plaques and tangles (Braak and Braak score of 6) and numerous Pick bodies (Halliday et al., 2005).

The mutation is absent from the gnomAD variant database (gnomAD v.2.1.1, May 2021).

Neuropathology

Neuropathology consistent with a diagnosis of AD was observed in multiple affected mutation carriers. 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. Pick bodies have been noted in some cases (Halliday et al., 2005).

Also, another carrier of the M146L mutation 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 substitution 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 levels and the Aβ42/Aβ40 ratio were found increased in conditioned media from M146L mutant fibroblasts and iPSC-derived neurons (Liu et a., 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), another 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).

The M146L (A>T) mutation, resulting in the same codon change, has also been found in AD patients. Of note, experiments describing the biological effects of M146L do not always specify which nucleotide change was tested. 

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

This mutation has been introduced into several mouse models of disease, including the single-transgenic PS1(M146L), the double-transgenic PS/APP, and the widely used 5xFAD, which also carries three APP mutations and the PSEN1 mutation L286V.

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References

Research Models Citations

1. PS1(M146L)
2. PS/APP

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
3. Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor 9 Sep 2016

Mutations Citations

1. PSEN1 M146L (A>T)

Paper Citations

1. Bruni AC, Bernardi L, Colao R, Rubino E, Smirne N, Frangipane F, Terni B, Curcio SA, Mirabelli M, Clodomiro A, Di Lorenzo R, Maletta R, Anfossi M, Gallo M, Geracitano S, Tomaino C, Muraca MG, Leotta A, Lio SG, Pinessi L, Rainero I, Sorbi S, Nee L, Milan G, Pappatà S, Postiglione A, Abbamondi N, Forloni G, St George Hyslop P, Rogaeva E, Bugiani O, Giaccone G, Foncin JF, Spillantini MG, Puccio G. Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. Neurology. 2010 Mar 9;74(10):798-806. Epub 2010 Feb 17 PubMed.
2. Borrello L, Cupidi C, Laganà V, Anfossi M, Conidi ME, Smirne N, Taverniti M, Guarasci R, Bruni AC. Angela R.: a familial Alzheimer's disease case in the days of Auguste D. J Neurol. 2016 Dec;263(12):2494-2498. Epub 2016 Oct 11 PubMed.
3. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
4. Bruni AC. Cloning of a gene bearing missense mutations in early onset familial Alzheimer's disease: a Calabrian study. Funct Neurol. 1998 Jul-Sep;13(3):257-61. PubMed.
5. Foncin JF, Salmon D, Supino-Viterbo V, Feldman RG, Macchi G, Mariotti P, Scoppetta C, Caruso G, Bruni AC. [Alzheimer's presenile dementia transmitted in an extended kindred]. Rev Neurol (Paris). 1985;141(3):194-202. PubMed.
6. Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
7. Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
8. Bergamini L, Pinessi L, Rainero I, Brunetti E, Cerrato P, Cosentino L, Vaula G, Bruni AC, Ermio C, Gei G. Familial Alzheimer's disease. Evidences for clinical and genetic heterogeneity. Acta Neurol (Napoli). 1991 Dec;13(6):534-8. PubMed.
9. Rainero I, Bergamini L, Bruni AC, Ferini-Strambi L, Foncin JF, Gei G, Macciardi F, Montesi MP, Pinessi L, Vaula G. A new Italian pedigree with early-onset Alzheimer's disease. J Geriatr Psychiatry Neurol. 1994 Jan-Mar;7(1):28-32. PubMed.
10. Sorbi S, Nacmias B, Forleo P, Piacentini S, Sherrington R, Rogaev E, St George Hyslop P, Amaducci L. Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439-40. PubMed.
11. 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.
12. 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.
13. Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.

Other Citations

1. 5xFAD

External Citations

1. gnomAD v.2.1.1

Further Reading