Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121550634 C>T
Position: (GRCh37/hg19):Chr11:121421343 C>T
dbSNP ID: rs1050845490
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CGA to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 16

Findings

This variant, which introduces a premature stop codon, was identified in a 91-year-old Alzheimer’s patient in a Dutch sample of 640 AD cases and 1268 controls. No additional carriers were seen in a pan-European sample of 1,255 cases and 1,938 controls from the European Early Onset Dementia Consortium (Holstege et al., 2017).

Subsequently, the variant was detected in a single Alzheimer’s case, described as a non-Hispanic white man, in a whole-exome sequencing study of more than 20,000 individuals (6,965 AD cases and 13,232 controls) from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer’s Disease Sequencing Project (ADSP), and the Institute of Genomic Medicine at Columbia University (Raghavan et al., 2018).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including the ADSP and the Dutch dataset cited above, this allele was observed five times among the AD cases (Holstege et al., 2022).

The R744Ter variant is classified as pathogenic by the criteria of Holstege et al., 2017 (Holstege et al., 2017).

Functional Consequences

Although often considered a neuronal protein, SORL1 was shown to be expressed by microglia from aged human brains (Olah et al., 2018) and mouse brains (Yang et al., 2021). When microglia-like cells derived from human embryonic stem cells were made homozygous for the R744Ter mutation through CRISPR gene editing, SORL1 expression was abolished and expression of APOE and TREM2 were upregulated (Liu et al., 2020). These cells showed defects in uptake of Aβ in vitro and in vivo when transplanted into mouse brains. Interestingly, the effect of the SORL1 mutation on Aβ phagocytosis depended upon APOE genotype: When the APOE genotype of the parental cell line was changed through CRISPR editing from E3/E4 to E3/E3, Aβ binding and uptake were restored to the levels seen in cells expressing wild-type SORL1.

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References

Paper Citations

1. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.
2. Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R, Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Jul;5(7):832-842. Epub 2018 May 24 PubMed.
3. 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.
4. Olah M, Patrick E, Villani AC, Xu J, White CC, Ryan KJ, Piehowski P, Kapasi A, Nejad P, Cimpean M, Connor S, Yung CJ, Frangieh M, McHenry A, Elyaman W, Petyuk V, Schneider JA, Bennett DA, De Jager PL, Bradshaw EM. A transcriptomic atlas of aged human microglia. Nat Commun. 2018 Feb 7;9(1):539. PubMed.
5. Yang HS, Onos KD, Choi K, Keezer KJ, Skelly DA, Carter GW, Howell GR. Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer's disease. Cell Rep. 2021 Feb 9;34(6):108739. PubMed.
6. Liu T, Zhu B, Liu Y, Zhang X, Yin J, Li X, Jiang L, Hodges AP, Rosenthal SB, Zhou L, Yancey J, McQuade A, Blurton-Jones M, Tanzi RE, Huang TY, Xu H. Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE. J Exp Med. 2020 Dec 7;217(12) PubMed.

Further Reading

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