Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr11:121460836 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GTC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 30

Findings

The D1389V variant was identified in a dataset from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ), the French national reference center for young Alzheimer patients (Nicolas et al., 2016; Nicolas et al., 2018). The carrier was 47 years old at symptom onset, with an APOE genotype of E3/E3 and no known family history of AD. In addition to the SORL1 D1389V variant, this patient also carried the R47H variant of TREM2.

No additional carriers were found among 852 early onset cases, 927 late-onset cases, and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Bellenguez et al., 2017).

This variant had been selected for genotyping in a North American sample of 217 sporadic early onset AD cases and 169 controls, based on its occurrence in the Exome Variant Server database as a nonsynonymous variant with a minor allele frequency <5 percent. The variant was not found in this cohort. Nor was it found by whole-exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study (Fernández et al., 2016).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including CNR-MAJ and ADESFR, this allele was observed once 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 1389 is a component of the Ca²⁺ cage in CR8.

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, D1502G, D1535N, D1545N, D1545G, D1545E. With the exception of D1267E, all carriers of these variants were Alzheimer’s cases.

This variant was predicted to be deleterious by SIFT, probably damaging by PolyPhen-2, and disease-causing by Mutation Taster (Nicolas et al., 2016).

In a study investigating the effects of SORL1 missense mutations on protein processing, the D1389V 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. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.
2. Nicolas G, Acuña-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, Rousseau S, Richard AC, Oud MS, Marguet F, Laquerrière A, Morris CM, Attems J, Smith C, Ansorge O, Al Sarraj S, Frebourg T, Campion D, Hannequin D, Wallon D, Gilissen C, Chinnery PF, Veltman JA, Hoischen A. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1632-1639. Epub 2018 Aug 13 PubMed.
3. Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.
4. Fernández MV, Black K, Carrell D, Saef B, Budde J, Deming Y, Howells B, Del-Aguila JL, Ma S, Bi C, Norton J, Chasse R, Morris J, Goate A, Cruchaga C, NIA-LOAD family study group, NCRAD. SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
5. 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.
6. 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.
7. 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.

Further Reading

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