Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121629498 G>A
Position: (GRCh37/hg19):Chr11:121500207 G>A
dbSNP ID: rs779578073
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 48

Findings

The variant was found in two of 5198 Alzheimer's cases—one of whom was classified as early onset—and one of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project (ADSP), consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including ADSP, this allele was observed three times—twice among the AD cases and once among the controls (Holstege et al., 2022).

Functional Consequences

Glutamate-2194 is located in SORL1’s cytoplasmic tail, within an acidic cluster (²¹⁹⁰DDLGEDDED²¹⁹⁸) that binds adaptor proteins (Nielsen et al., 2007; Schmidt et al., 2007; Burgert et al., 2013).

Data on the functional consequences of substitutions at this specific residue are lacking, but loss of function of the acidic cluster disturbs SORL1 trafficking, with concomitant effects on APP and Aβ. In CHO cells stably transfected with APP and SORL1 mutated to abolish the acidic cluster (all aspartates and glutamates in the DDLGEDDED sequence were changed to alanines), SORL1 binding to the adaptor protein PACS-1 was eliminated, APP accumulated at the cell surface, and levels of Aβ40 and Aβ42 were elevated in the culture medium, compared with cells transfected with APP and wild-type SORL1 (Schmidt et al., 2007). To investigate the effects of loss of the acidic cluster in vivo, transgenic mice were generated that carry human SORL1—either wild-type or mutated to eliminate the acidic cluster as described above—targeted to the Rosa26 locus, on a Sorl1-null background (Burgert et al., 2013). In the brains of both lines, SORL1 was primarily found in neurons, but the wild-type and mutant proteins differed in their subcellular localization, with the wild-type concentrated in Golgi compartments and the mutant protein shifting to early endosomes. When crossed with 5xFAD mice, an aggressive model of amyloidosis, mutant SORL1 did not affect levels of APP but led to increased amounts of Aβ40 and Aβ42. These findings can be explained if the acidic domain mediates retrograde sorting of a SORL1/APP complex from endosomes back to the Golgi/trans-Golgi network, thus protecting APP from processing in endosomal compartments.

Andersen and colleagues have predicted that substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023).

The E2194K variant was predicted to be tolerated by SIFT, but deleterious by Mutation Taster and PolyPhen-2 (Campion et al., 2019).

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References

Research Models Citations

1. 5xFAD (B6SJL)

Paper Citations

1. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
2. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
3. Nielsen MS, Gustafsen C, Madsen P, Nyengaard JR, Hermey G, Bakke O, Mari M, Schu P, Pohlmann R, Dennes A, Petersen CM. Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA. Mol Cell Biol. 2007 Oct;27(19):6842-51. PubMed.
4. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM, Willnow TE. SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem. 2007 Nov 9;282(45):32956-64. PubMed.
5. Burgert T, Schmidt V, Caglayan S, Lin F, Füchtbauer A, Füchtbauer EM, Nykjaer A, Carlo AS, Willnow TE. SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes. Mol Cell Biol. 2013 Nov;33(21):4308-20. PubMed.
6. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

Further Reading

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