Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121570255 G>A
Position: (GRCh37/hg19):Chr11:121440964 G>A
dbSNP ID: rs1298299676
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to AAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 23

Findings

The variant was found in two 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 three times among the AD cases (Holstege et al., 2022).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster, and ligand binding is Ca²⁺-dependent. In proteins with CR domains, each CR contains four amino acids whose acidic side chains, together with the backbone carbonyls of two additional residues, form an octahedral Ca²⁺ cage critical for proper folding of the domain. Residue 1108 is a component of the Ca²⁺ cage in CR1.

Andersen and colleagues predicted that variants affecting residues that contribute their acidic side chains to the Ca²⁺ cages are highly likely to increase AD risk (Andersen et al., 2023). Domain mapping of disease mutations revealed that several variants associated with medical conditions—in genes including LDLR (familial hypercholesterolemia), LRP2 (intellectual disability, Stickler syndrome), LRP5 (exudative vitreoretinopathy 4), TMPRSS3 (deafness), and TMPRSS6 (iron-refractory iron deficiency anemia)—occur in Ca²⁺-cage residues. Furthermore, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 Ca²⁺-cage variants significantly increased the risk of AD (OR = infinity), leading to the suggestion that these variants be considered causative for AD (Andersen et al., 2023).

The following Ca²⁺-cage variants are listed in the Alzforum database: D1108N, D1182N, D1219G, D1261G, D1267N, D1267E, D1345N, D1439N, D1502G, D1535N, D1545N, D1545G, D1545E. With the exception of D1267E, all carriers of these variants were Alzheimer’s cases.

The D1108N variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Campion et al., 2019).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

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.

Further Reading

No Available Further Reading