Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558785 G>A
Position: (GRCh37/hg19):Chr11:121429494 G>A
dbSNP ID: rs374275150
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

Three carriers of this variant—all Alzheimer’s cases—were found among 15,808 AD cases and 16,097 controls in a study that combined data from multiple European and American cohorts (Holstege et al., 2022). An additional three carriers—two Alzheimer’s cases and a control—were found when this dataset was expanded to 18,959 AD cases and 21,893 controls. Ages of onset ranged from 46 to 78 years (Holstege et al., 2023).

Functional Consequences

Arginine-953 is located in the fifth of the six “blades” that form SORL1’s YWTD β-propeller domain. Structural modeling of SORL1 and analysis of the crystal structures of homologous domains in LDLR, LRP4, and LRP6 suggest that arginine-953 is critical for the folding and stability of the β-propeller domain (Fazeli et al., 2023).

Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of arginine-953 are highly likely to associate with the risk of Alzheimer’s disease (Andersen et al., 2023; Fazeli et al., 2023). Five pathogenic variants were identified in homologous positions in three other proteins: a variant in LDLR linked to familial hypercholesterolemia 1; variants in LRP5 that were found in patients with osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy 4, or polycystic liver disease 4; and a variant in LRP4 believed to cause sclerosteosis.

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References

Paper Citations

1. 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.
2. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
3. Fazeli E, Child DD, Bucks SA, Stovarsky M, Edwards G, Yu C-E, Latimer C, Kitago Y, Bird T, Andersen O, Jayadev S, Young JE. A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting. 2023 Jul 05 10.1101/2023.07.01.547348 (version 2) bioRxiv.
4. 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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