Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558698 A>G
Position: (GRCh37/hg19):Chr11:121429407 A>G
dbSNP ID: rs377498269
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to AGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

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 four times—twice among the AD cases and twice among the controls (Holstege et al., 2022). An additional control carrier was found when this dataset was expanded to 18,959 AD cases and 21,893 controls (Holstege et al., 2023).

This variant was first reported in an individual with early onset Alzheimer’s disease (age of onset 58 years), from a family in which the disease showed autosomal dominant inheritance in the absence of mutations in APP, PSEN1, or PSEN2 (Pottier et al., 2012).

Subsequently, a total of four carriers—three AD cases and one control—were identified in a data set from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Campion et al., 2019). ADESFR contributed data to the 2022 study cited above.

Functional Consequences

Asparagine-924 is part of the “Shutter Binding NXI” (SBiN) motif in the YWTD-repeated β-propeller, a sequence involved in binding ligands containing an Asn-Ile pair separated by a variable residue (NXI-pair). As SORL1 contains five internal NXI-pairs, the SBiN motif may mediate intramolecular interactions within this protein. Based on domain mapping of disease mutations—pathogenic variants were identified in homologous positions in LDLR (linked to familial hypercholesterolemia 1) and LRP5 (found in patients with high bone mass or autosomal dominant osteopetrosis 1)—Andersen and colleagues predicted that mutations of asparagine-924 are moderately likely to have an effect on AD risk (Andersen et al., 2023).

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

In a study investigating the effects of SORL1 missense mutations on protein processing, the N924S variant did not affect the maturation (glycosylation) of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

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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. Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, Thomas-Anterion C, Michon A, Croisile B, Etcharry-Bouyx F, Berr C, Dartigues JF, Amouyel P, Dauchel H, Boutoleau-Bretonnière C, Thauvin C, Frebourg T, Lambert JC, Campion D. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; PubMed.
3. 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.
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.
5. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. PubMed.

Other Citations

1. Holstege et al., 2023

Further Reading

No Available Further Reading