Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121543625 C>T
Position: (GRCh37/hg19):Chr11:121414334 C>T
dbSNP ID: rs752726649
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to ATA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 13

Findings

This variant was found in a family of European ancestry with several members afflicted with Alzheimer’s disease (Cuccaro et al., 2016; Cukier et al., 2017; Kunkle et al., 2017). The variant did not segregate with disease in this family: Genotype data were available from four affected and three unaffected family members. All four affected individuals were heterozygous carriers of this variant, as were two of the non-affected family members (examined at 81 and 84 years of age). Three of the affected individuals (ages of onset 59, 73, and 82 years) had an APOE genotype of E3/E4, while the fourth (age of onset 81 years) was E3/E3; the three unaffected family members were APOE E3/E3.

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

Functional Consequences

The threonine-to-isoleucine substitution reduced SORL1 binding to APP in a heterologous expression system—HEK293 cells stably expressing APP with the Swedish mutation that were transfected with myc-tagged variants of SORL1 (Cuccaro et al., 2016). This resulted in more APP at the cell surface and elevated levels of Aβ42, sAPPα, and sAPPβ in the medium of cells expressing the T588I variant, compared with cells expressing wild-type SORL1.

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References

Paper Citations

1. Cuccaro ML, Carney RM, Zhang Y, Bohm C, Kunkle BW, Vardarajan BN, Whitehead PL, Cukier HN, Mayeux R, St George-Hyslop P, Pericak-Vance MA. SORL1 mutations in early- and late-onset Alzheimer disease. Neurol Genet. 2016 Dec;2(6):e116. Epub 2016 Oct 26 PubMed.
2. Cukier HN, Kunkle BK, Hamilton KL, Rolati S, Kohli MA, Whitehead PL, Jaworski J, Vance JM, Cuccaro ML, Carney RM, Gilbert JR, Farrer LA, Martin ER, Beecham GW, Haines JL, Pericak-Vance MA. Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. J Alzheimers Dis Parkinsonism. 2017 Aug;7(4) Epub 2017 Jul 31 PubMed.
3. Kunkle BW, Vardarajan BN, Naj AC, Whitehead PL, Rolati S, Slifer S, Carney RM, Cuccaro ML, Vance JM, Gilbert JR, Wang LS, Farrer LA, Reitz C, Haines JL, Beecham GW, Martin ER, Schellenberg GD, Mayeux RP, Pericak-Vance MA. Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport. JAMA Neurol. 2017 Sep 1;74(9):1113-1122. PubMed.
4. 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.

Further Reading

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