Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121629538 A>G
Position: (GRCh37/hg19):Chr11:121500247 A>G
dbSNP ID: rs1379473559
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to GGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 48

Findings

The variant was found in one of 5198 Alzheimer's cases and none 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 once among the AD cases (Holstege et al., 2022).

Functional Consequences

Aspartate-2207 is part of a sequence of amino acids at the C-terminal end of SORL1 that binds to GGAs (Golgi-associated, γ-adaptin homologous, ARF-interacting proteins). These adaptor proteins mediate anterograde trafficking of membrane-spanning proteins from the Golgi to endosomes. The minimal motif required for GGA binding appears to be aspartates- 2207 and 2208 followed by methionine-2211 (Jacobsen et al., 2002). Andersen and colleagues have predicted that substitutions at these positions are moderately likely to increase AD risk (Andersen et al., 2023).

The effects of disrupting the GGA-binding motif on SORL1 trafficking and APP processing have been investigated using transgenic mice. Mice were generated that carry human SORL1—either wild-type (SORL1^WT) or mutated to eliminate the GGA-binding motif (²²⁰⁷DDVPMV²²¹² -> ²²⁰⁷AAVPAA²²¹², “SORL1^GGA”)—targeted to the Rosa26 locus, on a Sorl1-null background (Dumanis et al., 2015). SORL1 was found primarily in neurons in the brains of these mice. Levels of SORL1^GGA were elevated, and the mutant protein showed increased localization to the trans-Golgi network and early endosomes, but loss from lysosomes, compared with SORL1^WT. When crossed with 5xFAD mice, an aggressive model of amyloidosis, mutant SORL1 led to increased amounts of Aβ40 and Aβ42 but not sAPPα or sAPPβ. These findings can be explained by a failure of SORL1-dependent targeting of Aβ to lysosomes for degradation in the mice expressing SORL1^GGA.

The D2207G variant was predicted to be deleterious by SIFT, 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. 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.
4. Dumanis SB, Burgert T, Caglayan S, Füchtbauer A, Füchtbauer EM, Schmidt V, Willnow TE. Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain. J Neurosci. 2015 Sep 16;35(37):12703-13. PubMed.

Other Citations

1. Jacobsen et al., 2002

Further Reading

No Available Further Reading