Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1, BS2, BS4, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:26051070 T>C
Position: (GRCh37/hg19):Chr21:27423386 T>C
dbSNP ID: rs145081708
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCT to CCT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 5

Findings

This rare variant has been found in both Alzheimer’s patients and unaffected elderly individuals. Unlike mutations responsible for familial autosomal dominant Alzheimer’s disease, which are located in exons 16 and 17 of APP, within or near the coding region for the Aβ peptide, this variant is in exon 5, in the extracellular domain of APP. Nevertheless, in model systems the mutation leads to increased production of Aβ—prompting the suggestion that the variant is a partially penetrant risk factor for AD (Zhang et al., 2021).

In their 2021 study, Zhang and colleagues reported six carriers of the S198P variant, three of whom were afflicted with AD and three who were unaffected (Zhang et al., 2021). Two of the AD cases were siblings in the NIMH AD Genetics Initiative Family Sample, with ages of onset 59 years (APOE genotype ε4/ε4) and 68 years (ε3/ε4); no other siblings were available for genotyping. The third affected carrier, age of onset 60 years and APOE genotype ε2/ε4, was found in the NIA Alzheimer’s Disease Sequencing Project (ADSP) case–control cohort of unrelated participants. Two unaffected carriers—ages 72 and 82 years at last examination and both heterozygous for ε4—were also found in the ADSP case–control cohort, while the third unaffected carrier—77 years old at last examination and homozygous for the ε3 allele of APOE—was identified in the ADSP family sample.

The S198P mutation was also found in a set of monozygotic triplets, two of whom were afflicted with AD (ages of onset 73 and 76 years) and the other unaffected at age 85, with APOE genotype ε3/ε4 (Zhang et al., 2019). Besides APP S198P,  the triplets carried 50 additional possibly damaging rare variants, including SORL1 W1563C and NOTCH3 H1235L. An offspring of one of the affected triplets developed AD at age 50 and was found to carry the S198P mutation.

The variant is found in the TOPMED and gnomAD databases with minor allele frequencies less than 0.001. In the gnomAD variant database (gnomAD v2.1.1, Oct 2021) it is particularly prevalent in individuals of Ashkenazi Jewish descent (142 alleles of a total of 177), but also found in individuals of Latino/Admixed American (16 alleles) and European (14 alleles) descent. Moreover, in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, it was present with an allele count of one in a total of 954 alleles (HEX, Oct 2021). It also appears in four entries in the ClinVar database, where it is classified as “benign” or “of uncertain significance.” 

Biological Effects

The S198P mutation in APP increased the production of Aβ in cultured cells and in a transgenic mouse model of amyloidosis (Zhang et al., 2021).

HEK293 cells that stably express the 695-amino acid isoform of human APP (APP695) with both the AD-linked Swedish mutation and the S198P mutation secreted more Aβ40 and Aβ42 than did cells expressing APP with only the Swedish mutation. Introduction of the S198P mutation appeared to accelerate folding of APP and translocation from the endoplasmic reticulum to compartments where β-secretase is active.

In order to examine the effects of the S198P mutation in the mammalian brain, Zhang et al. created transgenic mice that express human APP695 with both the Swedish and S198P mutations (Zhang et al., 2021). These APP695Swe/S198P mice were then crossed with mice expressing human presenilin-1 with the AD-linked exon 9 deletion (PS1ΔE9) (Lee et al., 1997). Compared with mice that express APP695Swe/PS1ΔE9, mice that also carry the S198P mutation generated more Aβ and showed accelerated deposition of amyloid plaques.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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

Comments

1. • Sam Gandy
     Icahn School of Medicine at Mount Sinai
   • Michelle Ehrlich
     Icahn School of Medicine at Mount Sinai
   • Posted: 27 Aug 2021
   • Paper: An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo.

   Rare pathogenic APP mutation causes ectodomain kinking, leading to accelerating intracellular transport, and enhancing Aβ accumulation

   In this paper, Sangram Sisodia, University of Chicago, Rudolph Tanzi, Massachusetts General Hospital, Charlestown, Massachusetts, and their colleagues describe a rare new Alzheimer’s mutation, APP S198P, that resides not within or flanking the Aβ domain but instead in the Aβ precursor protein (APP) ectodomain, where it acts as a helix-breaker. Pathogenicity was validated in experiments showing enhanced accumulation of Aβ amyloid in APP S198P transgenic mouse brain. In cultured cells, APP S198P underwent accelerated ER folding and rapid delivery to endosomal-lysosomal compartments, leading to enhanced Aβ accumulation.

   Precisely how is the APP S198P mutation exerting its effects on APP metabolism? Serine 198 is located in a highly flexible and extended acidic-rich domain (Ala 191-Val 290) that lies between two distinct structural domains of ~160 amino acids and ~190 amino acids in the APP 695 ectodomain, termed the E1 and E2, respectively (Coburger et al., 2013). First author Xulun Zhang and colleagues demonstrated that cellular APP C-terminal fragments (CTFs) and extracellular, soluble APP derived from the full-length APP S198P precursor containing the Swedish mutation (sAPPSwe-S198P) appeared at the earliest time points and accumulated to higher levels in pulse-chase experiments compared with the rate of production and accumulation of these metabolites derived from full-length APPSwe that harbored the wild-type serine at position 198.

   Moreover, Zhang and colleagues report pulse-chase/immunoprecipitation studies suggesting that transient folding intermediates are made faster in cells expressing APPSwe S198P than in cells expressing APPSwe, a key finding that provides compelling support that the S198P variant undergoes accelerated folding. In support of this idea, pulse-chase studies using the P2-1 antibody, which is specific for a sulfhydryl-dependent structural epitope in the N-terminal E1 domain of APP, revealed that, indeed, folding of this domain occurred faster in cells expressing the APPSweS198P variant than in cells expressing APPSwe. The authors propose that the proline at position 198 enhances the rate of folding and the exit of newly synthesized APPSweS198P from the endoplasmic reticulum to the Golgi and to late compartments where BACE1 and γ-secretase are active.

   How can the rate of folding of the APPSwe S198P variant be accelerated relative to APPSwe? The determining factor is the introduction of proline, an amino acid that either breaks or kinks a helix, both because it cannot donate an amide hydrogen bond (having no amide hydrogen), and because its bulky pyrrolidine ring restricts the available conformational space. To any structural biologist playing the word-association game Password, “proline” would immediately evoke the response “helix breaker.” Interestingly, an analysis of all proline residues and their local conformations extracted from the Brookhaven Protein Data bank (MacArthur and Thornton, 1991) revealed that the residue preceding proline plays an important role in determining conformation of the protein. When proline follows an aspartate residue, there is a very high probability of the α conformation being adopted (α:β=9:1). In the case of APP, the residue immediately preceding residue 198 is aspartate.

   Zhang and colleagues offer a highly speculative model that the Asp-Pro pair promotes the generation of a local α-helix that enhances the rate of folding of the surrounding E1 and E2 domains and the adjacent flexible domain. Their pulse-chase studies using the sulfhydryl-dependent, structural-epitope-specific antibody, mAbP2-1 support this assertion by showing preferential binding to APPSwe S198P over APPSwe.

   References:

   Coburger I, Dahms SO, Roeser D, Gührs KH, Hortschansky P, Than ME. Analysis of the overall structure of the multi-domain amyloid precursor protein (APP). PLoS One. 2013;8(12):e81926. Epub 2013 Dec 4 PubMed.

   MacArthur MW, Thornton JM. Influence of proline residues on protein conformation. J Mol Biol. 1991 Mar 20;218(2):397-412. PubMed.

   View all comments by Michelle Ehrlich

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References

Mutation Position Table Citations

1. PSEN1 S290 Mutations 28 Jun 2013

Research Models Citations

1. APPswe/PSEN1dE9 (line 85)

Paper Citations

1. Zhang X, Zhang CM, Prokopenko D, Liang Y, Zhen SY, Weigle IQ, Han W, Aryal M, Tanzi RE, Sisodia SS. An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo. J Exp Med. 2021 Jun 7;218(6) PubMed.
2. Zhang M, Dilliott AA, Khallaf R, Robinson JF, Hegele RA, Comishen M, Sato C, Tosto G, Reitz C, Mayeux R, George-Hyslop PS, Freedman M, Rogaeva E. Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets. Brain. 2019 Nov 1;142(11):3375-3381. PubMed.
3. Lee MK, Borchelt DR, Kim G, Thinakaran G, Slunt HH, Ratovitski T, Martin LJ, Kittur A, Gandy S, Levey AI, Jenkins N, Copeland N, Price DL, Sisodia SS. Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med. 1997 Jul;3(7):756-60. PubMed.

Other Citations

1. HEX

External Citations

1. gnomAD v2.1.1
2. ClinVar
3. CADD v.1.6

Further Reading