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. Indeed, the variant was classified as most likely having reduced penetrance, with an allele count of three, and a frequency of 0.0012 percent in the gnomAD variant database (Koriath et al., 2018). In the non-neuro subsection of gnomAD, the variant has an allele count of 2 and appears at 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 age of onset (Miranda et al., 2018; Jun 2018 news).

The G206A mutation 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 ethnicity (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 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).

The mutation was also found in one individual of a cohort of 111 pathologically confirmed cases of dementia with Lewy bodies (DLB). The patient was a woman diagnosed with DLB at age 56 who died at age 64 with robust AD pathology revealed at autopsy (Geiger et al., 2016).

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).

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, however, revealed a decrease in both Aβ40 and Aβ42 production and an increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

News Citations

1. Synaptojanin 1 Gene Affects Age of Onset in Familial AD, Memory in Mice 15 Jun 2018
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

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. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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. gnomAD (non-neuro) v.2.1.1

Further Reading