Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121478137 A>G
Position: (GRCh37/hg19):Chr11:121348846 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 3

Findings

This variant was identified in a French early onset Alzheimer’s patient from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ), the French national reference center for young Alzheimer patients (Pottier et al., 2012; Nicolas et al., 2016). The carrier, 46 years old at symptom onset and APOE genotype of E3/E3, has a family history consistent with an autosomal dominant pattern of inheritance, but no identified mutations in APP, PSEN1, or PSEN2. The variant was not found in a group of 1500 ethnically matched controls (Pottier et al., 2012).

No additional carriers were found among 852 early onset AD cases, 927 late-onset AD cases, and 1,273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Bellenguez et al., 2017).

This variant was among 54 selected for genotyping in a North American cohort of 217 sporadic early onset AD cases and 169 controls. The variant was not found in this cohort (Fernández et al., 2016). Nor was it found by whole- exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study.

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

In a study investigating the effects of SORL1 missense mutations on protein processing, the Y141C variant did not affect the maturation (glycosylation) or trafficking of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

The effects of this variant were also studied in human neurons derived from iPSCs in which CRISPR/Cas9 gene editing was used to introduce the Y141C mutation (Mishra et al., 2022). Levels of SORL1 protein were similar in neurons derived from the parental cell line and neurons heterozygous for the Y141C variant. Neurons carrying the variant had enlarged early endosomes and increased levels of secreted Aβ40 and Aβ42, compared with those derived from the parental line, but these effects were not as extreme as those seen in isogenic SORL1-knockout iPSC-derived neurons. It should be noted that the parental cell line is homozygous for three SNPs (rs668387, rs689021, and rs641120) in linkage disequilibrium within intron 6 of SORL1—a haplotype reported to associate with an increased risk of AD (Rogaeva et al., 2007)—and that the APOE genotype is E3/E4 (Young et al., 2015; Knupp et al., 2020).

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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. 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.
2. 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.
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. 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.
7. Mishra S, Knupp A, Kinoshita C, Martinez R, Theofilas P, Young JE. Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer's gene SORL1. 2022 Sep 26 10.1101/2022.07.31.502217 (version 2) bioRxiv.
8. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
9. Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, Herrera C, Israel MA, Yuan SH, Edland SD, Goldstein LS. Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell. 2015 Apr 2;16(4):373-85. Epub 2015 Mar 12 PubMed.
10. Knupp A, Mishra S, Martinez R, Braggin JE, Szabo M, Kinoshita C, Hailey DW, Small SA, Jayadev S, Young JE. Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing. Cell Rep. 2020 Jun 2;31(9):107719. PubMed.

Further Reading

No Available Further Reading