Mutations

PSEN1 G206A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, BS4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659420 G>C
dbSNP ID: rs63750082
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to GCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was first identified in 2001 in a group of families from Puerto Rico and the Dominican Republic (Athan et al., 2001; Rogaeva et al., 2001). It is now linked to Alzheimer's disease in more than 70 families of Caribbean-Hispanic ancestry (Lee et al., 2014). The mutation is associated with a variable age at onset, generally ranging from about 40 to 73 years of age, with some individuals remaining free of clinical symptoms into their 90s suggesting reduced penetrance. 

The G206A variant was first reported in five of 414 patients screened for familial Alzheimer’s disease (Rogaeva et al., 2001). The five mutation carriers represented four putatively unrelated families (two were siblings). All five carriers were of Hispanic ancestry (see note in Athan et al., 2001), but additional demographic and clinical details were not reported.

In a study of 19 Caribbean-Hispanic families affected by early onset AD, eight probands were found to carry the G206A mutation. The families all originated from Puerto Rico and the Dominican Republic, and microsatellite testing revealed a common ancestor. The mutation did not strictly segregate with disease; five family members had AD but were not mutation carriers. However, the mean age at onset was earlier in mutation carriers (54.5 ± 7.1 years) than in non-carriers (68.9 ± 9.5 years), suggesting that disease in the latter group may have been sporadic (three were homozygous for APOE4) (Athan et al., 2001).

Further underscoring the prevalence of this mutation in Hispanics with early onset AD, 13 of 27 EOAD cases identified in Florida were found to carry the G206A mutation. The average age of onset was 54.8 (range: 42-63) and average age at death was 62.2 (range: 50-70 years). Out of 63 Hispanics with late-onset AD, none carried this mutation. Of the 13 mutation carriers, two were female, and 11 had a known family history of AD. Haplotype-sharing analysis confirmed a common ancestor for all G206A mutation carriers in the cohort (Ravenscroft et al., 2016).

In a study of 283 Hispanic patients assessed at an Alzheimer’s Disease Center in Philadelphia, 19 carried the PSEN1 G206A mutation and were diagnosed with dementia (17 AD, one vascular dementia, one frontotemporal dementia). Compared with noncarriers with AD, these individuals had younger ages of onset, lower frequency of APOE ε4 genotype, and lower rates of hypertension. The mean age of onset for carriers was 59.6. Carrier performance in psychometric tests was similar to that of non-carriers. In three mutation carriers, total tau and phospho-tau levels in the CSF were abnormally elevated, and two of the three had abnormally low Aβ levels (Arnold et al., 2013).

Subsequent studies identified late-onset AD cases, as well as evidence of reduced penetrance. For example, a U.S.-based study identified four individuals with sporadic late-onset AD from a case-control cohort of the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 5,844 cases and 4,767 controls (Fernández et al., 2017). One of these carriers was of European American origin within an age at onset of 63 years and three were of Hispanic ancestry with a mean age at onset of 70 years. Moreover, a preprint describing analyses of a newer release from the ADSP, including data from 13,825 AD cases and 14,715 controls, identified 26 carriers: 21 AD cases, one control, and four individuals with unknown neurological status (Wang et al., 2023). Two of these carriers were inferred to be siblings.

Interestingly, as reported in a preprint, G206A was identified in a 3Mb region that includes 44 low-frequency variants associated with AD in Hispanics, but not in African Americans who had a higher overall frequency of these variants (Lee et al., 2023). In this study, based on data from the Alzheimer’s Disease Sequencing Project (ADSP), G206A was found only in Hispanics: in 17 AD patients, and a healthy 74-year-old woman. Only two were inferred to be related. Surprisingly, principal components analysis indicated the G206A variant is part of an African-derived haplotype, even though it was absent from African Americans in this group and, globally, the Hispanic carriers’ genomes were more closely related to Puerto Rican reference samples, with a high proportion of European ancestry. One possibility is that the variant arose in Puerto Rico in an individual carrying the African haplotype.

Also of note, G206A has been identified in a family from the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). Whether this family has Hispanic ancestry is unknown. The proband was a woman whose AD symptoms started at age 69. Her deceased mother had been affected, as well as a nephew, who carried the mutation and had an age at onset of 60 years. A brother of the latter was a non-carrier and remained unaffected at age 65.

Phenotypic variability has been associated with G206A. As noted above, it has been identified in a case of vascular dementia and of frontotemporal dementia (FTD) (Arnold et al., 2013). It was also found in a woman diagnosed with dementia with Lewy bodies (DLB) at age 56 who died at age 64 having both DLB and AD pathologies (Geiger et al., 2016). Moreover, cases of AD with atypical phenotypes have also been reported. For example, a carrier diagnosed with early onset AD had severe neuroleptic sensitivity, a trait commonly associated with DLB (Cercy et al., 2008) and another, also diagnosed with early onset AD, had symptoms of FTD, including psychosis with hallucinations and parasomnia (Venditto et al., 2021).

Also of note, four G206A carriers have been diagnosed with rapidly progressive AD (rpAD), two of whom were pathologically confirmed (Wang et al., 2024). This condition, characterized by very rapid progression of dementia and/or a shortened lifespan, appears to be distinct from typical AD at the molecular level. One of the rpAD cases, a G206A homozygote, died less than a year after disease onset, at age 42.

G206A was reported in the gnomAD variant database at a frequency of 0.000012 with an allele count of three. This frequency was considered consistent with reduced penetrance (Koriath et al., 2018). In the non-neuro subsection of gnomAD, the variant had an allele count of 2 and a frequency of 0.000009609 (gnomAD (non-neuro) v.2.1.1, July 2021).

Variants in different genes, such as the gene encoding the lipid phosphatase synaptojanin 1, may contribute to the high variability in phenotypes and ages of onset associated with G206A (Miranda et al., 2018; Jun 2018 news).

Neuropathology

Seven G206A mutation carriers from Florida and one from Pennsylvania came to autopsy. All had typical AD neuropathology including extensive plaques and tangles (Ravenscroft et al., 2016; Arnold et al., 2013). In addition, MRI revealed a pattern of cortical atrophy consistent with AD and 18FDG-PET showed temporo-parietal hypometabolism in three mutation carriers (Arnold et al., 2013). However, in one carrier, a woman with early onset AD including FTD-like symptoms, MRI revealed alterations described as mimicking limbic encephalitis, including mild diffuse volume loss and mesial temporal hyperintensities (Venditto et al., 2021).

Biological Effect

When co-expressed in HEK-293 cells expressing APP with the Swedish mutation, the mutant presenilin-1 produced a 2.2-fold increase in secreted Aβ42 compared with cells expressing wild-type presenilin-1. Secreted Aβ40 levels were comparable between the two cell lines (Athan et al., 2001). In vitro experiments using isolated proteins also revealed an increase in the Aβ42/Aβ40 ratio, although production of both peptides was reduced (Sun et al., 2017). Cleavage rates in this in vitro assay may be artificially low compared with cell-based systems (Liu et al., 2021).

A subsequent study that examined the full set of Aβ peptides generated by PSEN1 activity in transfected cells, revealed a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Also, like other pathogenic mutations, this variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the standard Aβ42/Aβ40 ratio for distinguishing between control and AD samples. Moreover, a follow-up study reported in a preprint, combined the Aβ (37 + 38 + 40) / (42 + 43) ratio with the commonly used Aβ42/Aβ40 ratio to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This composite score (61.38 for G206A) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in this residue could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news). In silico algorithms predicted this variant is probably damaging (Polyphen) and deleterious (SIFT) (gnomAD (non-neuro) v.2.1.1, July 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic*

*Carriers of this variant had heterogenous phenotypes, including healthy aged individuals, suggestive of reduced penetrance.

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.

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. G206A: 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.

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.

BS4-S

Lack of segregation in affected members of a family. G206A: Non-affected carriers and affected non-carriers reported, although the latter had later disease onset and 3/5 were APOE4 homozygotes.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 19 Jan 2024

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References

News Citations

  1. Synaptojanin 1 Gene Affects Age of Onset in Familial AD, Memory in Mice
  2. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  3. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PubMed.
  2. 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.
  3. Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Williamson J, Nagy P, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 PubMed.
  4. Ravenscroft TA, Pottier C, Murray ME, Baker M, Christopher E, Levitch D, Brown PH, Barker W, Duara R, Greig-Custo M, Betancourt A, English M, Sun X, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Rademakers R. The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida. Am J Neurodegener Dis. 2016;5(1):94-101. Epub 2016 Mar 1 PubMed.
  5. Arnold SE, Vega IE, Karlawish JH, Wolk DA, Nunez J, Negron M, Xie SX, Wang LS, Dubroff JG, McCarty-Wood E, Trojanowski JQ, Van Deerlin V. Frequency and Clinicopathological Characteristics of Presenilin 1 Gly206Ala Mutation in Puerto Rican Hispanics with Dementia. J Alzheimers Dis. 2013 Jan 1;33(4):1089-95. PubMed.
  6. Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A, NIA-LOAD family study group, NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017 Nov;13(11):e1007045. PubMed.
  7. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, TheAlzheimer'sDiseaseSequencingProject, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
  8. Lee W-P, Choi SH, Shea MG, Cheng P-L, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, DeJager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang L-S, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. 2023 Sep 02 10.1101/2023.09.01.23294953 (version 1) medRxiv.
  9. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  10. Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, Rosenthal LS, Pantelyat A, Gibbs JR, Albert MS, Hernandez DG, Hillis AE, Stone DJ, Singleton AB, North American Brain Expression Consortium, Hardy JA, Troncoso JC, Scholz SW. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016 Oct;94:55-62. Epub 2016 Jun 14 PubMed.
  11. Cercy SP, Sadowski MJ, Wisniewski T. Prominent neuroleptic sensitivity in a case of early-onset Alzheimer disease due to presenilin-1 G206A mutation. Cogn Behav Neurol. 2008 Sep;21(3):190-5. PubMed.
  12. Venditto JG, Bender E, Lichtenstein ML. Psychosis in a Middle-aged Woman: A Case of Presenilin-1 p.Gly206Ala Alzheimer Disease. Neurol Clin Pract. 2021 Aug;11(4):e573-e575. PubMed.
  13. Wang P, Lynn A, Miskimen K, Song YE, Wisniewski T, Cohen M, Appleby BS, Safar JG, Haines JL. Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease. Alzheimers Dement. 2024 Mar;20(3):2034-2046. Epub 2024 Jan 7 PubMed.
  14. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  15. Miranda AM, Herman M, Cheng R, Nahmani E, Barrett G, Micevska E, Fontaine G, Potier MC, Head E, Schmitt FA, Lott IT, Jiménez-Velázquez IZ, Antonarakis SE, Di Paolo G, Lee JH, Hussaini SA, Marquer C. Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Rep. 2018 Jun 5;23(10):2967-2975. PubMed.
  16. 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.
  17. 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.
  18. 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.
  19. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
  20. 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.

Other Citations

  1. Swedish mutation

External Citations

  1. Venditto et al., 2021
  2. gnomAD (non-neuro) v.2.1.1

Further Reading

Papers

  1. 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.
  2. Poblete J, Dokuru D, Coppola G, Ortiz F, Medina LD, Vinters HV, Ringman JM. Historical Migration revealed through a Case of Autosomal Dominant Alzheimer's Disease. P R Health Sci J. 2019 Sep;38(3):144-147. PubMed.
  3. Medina LD, Woo E, Rodriguez-Agudelo Y, Chaparro Maldonado H, Yi D, Coppola G, Zhou Y, Chui HC, Ringman JM. Reaction time and response inhibition in autosomal dominant Alzheimer's disease. Brain Cogn. 2021 Feb;147:105656. Epub 2020 Dec 10 PubMed.
  4. Wojtas A, Heggeli KA, Finch N, Baker M, Dejesus-Hernandez M, Younkin SG, Dickson DW, Graff-Radford NR, Rademakers R. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.
  5. Bartoletti-Stella A, Tarozzi M, Mengozzi G, Asirelli F, Brancaleoni L, Mometto N, Stanzani-Maserati M, Baiardi S, Linarello S, Spallazzi M, Pantieri R, Ferriani E, Caffarra P, Liguori R, Parchi P, Capellari S. Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease. Front Aging Neurosci. 2022;14:969817. Epub 2022 Sep 5 PubMed.

Protein Diagram

Primary 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. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PubMed.

Other mutations at this position

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Alzpedia

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