Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558767 C>T
Position: (GRCh37/hg19):Chr11:121429476 C>T
dbSNP ID: rs143571823
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

This variant was identified in a family- and cohort-based study of Caribbean Hispanics (Vardarajan et al., 2015) where it was found in four of 151 families examined. Joint linkage and association analysis, a method that allows researchers to analyze together data from families and unrelated subjects, showed that this variant  was associated with Alzheimer’s disease and that it segregated with disease under a dominant affecteds only model.

One ADNI control subject was found to be a heterozygous carrier of this variant (Vardarajan et al., 2015).

Subsequently, this variant was reported in two of 5198 AD cases 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 once among the AD cases and once among the controls (Holstege et al., 2022).

Descriptions of the clinical phenotypes of T947M carriers are limited. One carrier, with an age of onset of 90 years and an APOE genotype of E3/E4, was noted to exhibit parkinsonian features in addition to Alzheimer’s-like dementia (Cuccaro et al., 2016).

Functional Consequences

The effects of the SORL1 T947M variant were studied in HEK293 cells stably expressing human APPSwe and transfected with human SORL1 (Vardarajan et al., 2015). Only about a quarter of the amount of SORL1 protein, but three times the amount of APP, was found on the surface of cells transfected with the T947M variant compared with cells transfected with wild-type SORL1. This finding suggests that, by failing to reach the cell surface, mutant SORL1 was unable to bind APP and direct it to the retromer-recycling endosome pathway. Indeed, in co-immunoprecipitation experiments, mutant SORL1 protein bound only about a third as much APP as did wild-type protein. Altered APP trafficking in turn resulted in elevated levels of APP cleavage products: approximately double the levels of Aβ40 and Aβ42 and about 2.5-fold the levels of sAPPα and sAPPβ were released into the culture medium of cells transfected with T947M SORL1 compared with cells transfected with wild-type SORL1.

SORL1 has been shown to interact with the EphA4 receptor tyrosine kinase and to inhibit ligand-induced activation of EphA4 (Huang et al., 2017). Compared with wild-type SORL1, the T947M variant more weakly interacted with EphA4 and less effectively inhibited ligand-induced receptor activation.

The threonine-to-methionine substitution was predicted to be deleterious by SIFT and PolyPhen-2, but neutral by Mutation Taster (Campion et al., 2019).

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References

Paper Citations

1. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. PubMed.
2. 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.
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. 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.
5. Huang TY, Zhao Y, Jiang LL, Li X, Liu Y, Sun Y, Piña-Crespo JC, Zhu B, Masliah E, Willnow TE, Pasquale EB, Xu H. SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration. J Exp Med. 2017 Dec 4;214(12):3669-3685. Epub 2017 Nov 7 PubMed.

Further Reading

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