Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121627707 G>A
Position: (GRCh37/hg19):Chr11:121498416 G>A
dbSNP ID: rs372233947
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 47

Findings

This variant was identified in a screen of 124 Alzheimer’s patients with a family history of Alzheimer’s disease (at least one affected first-degree relative), recruited from a memory clinic in Madrid (Gómez-Tortosa et al., 2018). The carrier began exhibiting symptoms at 68 years of age and was 82 years old at the time of publication of her mutation. In addition to Alzheimer’s-like dementia, she also exhibits Parkinsonism. Her APOE genotype is E3/E4. DNA was available from one unaffected sibling of the proband, and this individual does not carry the variant. Another carrier, aged 75 years, was found in a control group of 200 Spanish individuals 69 to 95 years of age.

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 once among the AD cases (Holstege et al., 2022). No additional carriers were found when this dataset was expanded to 18,959 AD cases and 21,893 controls (Holstege et al., 2023).

The A2173T variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017) but as likely benign by the guidelines of the American College of Genetics and Genomics.

Functional Consequences

Alanine-2173 is located in SORL1’s cytoplasmic tail, within the ²¹⁷²FANSHY²¹⁷⁷ motif, a strictly conserved sequence necessary for binding the retromer complex (Fjorback et al., 2012). Andersen and colleagues have predicted that substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023).

Data on the functional consequences of substitutions at this specific residue are lacking. However, in vivo and in vitro studies showed that when the FANSHY domain was mutated to disrupt retromer binding, SORL1 accumulated in endosomes and was depleted from the Golgi/trans-Golgi network, while levels of APP cleavage products Aβ40, Aβ42, sAPPα, and sAPPβ increased (Fjorback et al., 2012; Dumanis et al., 2015). These findings can be explained if retromer-dependent sorting of SORL1 and its ligand APP from endosomes back to the Golgi/trans-Golgi network protects APP from processing in endosomal compartments.

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References

Paper Citations

1. Gómez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Pérez B, Ordás C, Agüero P, Guerrero-López R, Pérez-Pérez J. SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. 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. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
4. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.
5. Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR, Willnow TE, Christensen EI, Mobley WB, Nykjaer A, Andersen OM. Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. 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. Dumanis SB, Burgert T, Caglayan S, Füchtbauer A, Füchtbauer EM, Schmidt V, Willnow TE. Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain. J Neurosci. 2015 Sep 16;35(37):12703-13. PubMed.

Further Reading

No Available Further Reading