Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121588112 C>T
Position: (GRCh37/hg19):Chr11:121458821 C>T
dbSNP ID: rs781023219
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 28

Findings

The R1303C variant was identified in a Swedish family with a history of dementia, where the variant appeared to segregate with disease (Thonberg et al., 2017). In a two-generation pedigree, six siblings and one of their parents exhibited signs of dementia, with age of onset ranging from 51 to 68 years. Four of the siblings were clinically diagnosed with AD and the fifth with pre-senile dementia; the sixth sibling did not receive a clinical diagnosis prior to death but exhibited symptoms consistent with dementia. The parent was clinically diagnosed with senile dementia. All five affected individuals who were genotyped—the parent and four siblings—carried the R1303C mutation and were APOE E3/E4. Two unaffected siblings—one of whom died at age 85 years and the other who was last evaluated at age 77—did not carry the SORL1 mutation and were APOE genotypes E3/E4 and E3/E3, respectively.

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including the Alzheimer Disease Exome Sequencing France (ADESFR) project, this allele was observed twice among the AD cases and once among the controls (Holstege et al., 2022). An earlier report had identified a heterozygous carrier of the R1303C variant in the ADESFR dataset. This carrier was one of  852 early onset cases included in this cohort; no additional carriers were found among the 927 late-onset Alzheimer’s cases or 1273 controls in this study (Bellenguez et al., 2017; Campion et al., 2019).

The R1303C variant was classified as likely pathogenic by the criteria of the American College of Medical Genetics and Genomics (Thonberg et al., 2017).

Neuropathology

Neuropathological examinations were performed on autopsy specimens from two of the Swedish R1303C carriers and confirmed the clinical diagnosis of AD: Both cases met the CERAD criteria for AD and were Braak stages V-VI.

SORL1 immunoreactivity was evaluated in tissue sections from these two R1303C carriers and in sections from unrelated sporadic AD cases and controls, using a panel of antibodies. Antibody-dependent staining patterns were qualitatively similar in the carriers and at least some of the other AD cases and controls—and included punctate staining of the somata and dendrites of pyramidal neurons in the frontal cortex and the hippocampus, glial staining, and staining of extracellular deposits.

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Each CR contains six conserved cysteines. Variants resulting in an odd number of cysteines—either through substitution of one of these six cysteines or mutation of another residue to cysteine, as in R1303C—may disrupt disulfide bridging. Based on domain mapping of disease mutations, Andersen and colleagues predicted that variants containing an odd number of cysteines in a CR domain (ONC variants) are highly likely to increase AD risk (Andersen et al., 2023): Approximately 40 percent of variants in the low-density lipoprotein receptor gene (LDLR) linked to familial hypercholesterolemia are ONC variants, and ONC variants in the LDL receptor related protein 4 (LRP4) and LRP5 genes have been linked to Cenani–Lenz syndactyly syndrome and exudative vitreoretinopathy 4, respectively. Indeed, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 ONC variants significantly increased the risk of AD (OR = 6.31 95% CI: 2.45 -16.24, p=5.1x10^-6; Fisher Exact test) (Andersen et al., 2023).

The co-localization of APP and SORL1 in autopsied brains from two R1303C carriers, four sporadic AD cases, and four control subjects was assessed using a proximity ligation assay (Thonberg et al., 2017). The extent of co-localization of SORL1 and APP was similar in mutation carriers and controls, but less than that seen in sporadic AD.

In a study investigating the effects of SORL1 missense mutations on protein processing, the R1303C variant did not affect the maturation (glycosylation) of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

This mutation was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Rovelet-Lecrux et al., 2021).

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References

Paper Citations

1. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindström AK, Johansson C, Björkström J, Thordardottir S, Sleegers K, Van Broeckhoven C, Rönnbäck A, Graff C. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun. 2017 Jun 9;5(1):43. 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. 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. 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.
5. 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.
6. 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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