Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121522924 G>C
Position: (GRCh37/hg19):Chr11:121393633 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to CGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 11

Findings

The G511R variant was identified in a family enrolled in the Centre National de Référence -Malades Alzheimer Jeunes (CNR-MAJ), the French National Reference Center for Young Alzheimer Patients, with a pedigree consistent with an autosomal dominant pattern of inheritance, but no known mutations in APP, PSEN1, or PSEN2 (Pottier et al., 2012; Nicolas et al., 2016; Schramm et al., 2022). The proband (60 years old at symptom onset, APOE genotype E3/E3), his mother (age of onset 63 years; APOE E3/E3), and maternal grandmother (age of onset 65) were affected. The mother also carried the G511R mutation; genotype information was not available from the grandmother. The proband’s father was also affected (age of onset 73, SORL1 genotype unknown). The variant was not found in a group of 1,500 ethnically matched controls (Pottier et al., 2012).

The G511R variant was also found in an Italian AD case from the European Early Onset Dementia Consortium, with an age at onset of 55 years and no known family history of AD (Verheijen et al., 2016).

No additional carriers were found among 852 early onset AD cases, 927 late-onset cases, or 1,273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Bellenguez et al., 2017). Nor was this variant found in a North American cohort of 217 sporadic early onset AD cases and 169 controls (Fernández et al., 2016) or a Dutch cohort of 640 AD cases and 1,268 controls (Holstege et al., 2017).

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). CNR-MAJ, ADESFR, and the cohorts comprising the Dutch sample cited above all contributed data to this study.

The G511R variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

In a study investigating the effects of SORL1 missense mutations on protein processing, the G511R variant did not affect the maturation (glycosylation) or trafficking of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

However, the mutation abolished binding of β-amyloid (Aβ) to the SORL1 VPS10P domain expressed in HEK293 cells and slowed the intracellular breakdown of Aβ in SH-SY5Y cells overexpressing human APP695 and SORL1, apparently by impairing Aβ trafficking to lysosomes (Caglayan et al., 2014).

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 G511R mutation (Mishra et al., 2022). Levels of SORL1 protein were similar in neurons derived from the parental cell line and neurons heterozygous for the G511R 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. The enlarged endosomes might reflect a “traffic jam” caused by the accumulation of molecular cargos that depend upon SORL1 to exit the endosome, consistent with the impaired trafficking of Aβ to lysosomes suggested by Caglayan et al. 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).

Analysis of the crystal structure of the VPS10p domain suggests an explanation for the loss of Aβ binding when glycine-511 is replaced with arginine (Kitago et al., 2015). While this glycine is not itself part of the Aβ-binding sequence, the so-called “L2 loop,” its position indicates that it may have a role in controlling the conformation or stability of L2.

The G511R variant was predicted to be damaging by three algorithms: PolyPhen-2, SIFT, and Mutation Taster (Bellenguez et al., 2017; Nicolas et al., 2016; Verheijen et al., 2016).

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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. Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.
4. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, Kitago Y, Füchtbauer EM, Füchtbauer A, Holtzman DM, Takagi J, Willnow TE. Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci Transl Med. 2014 Feb 12;6(223):223ra20. PubMed.
11. 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.
12. 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.
13. 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.
14. 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.
15. Kitago Y, Nagae M, Nakata Z, Yagi-Utsumi M, Takagi-Niidome S, Mihara E, Nogi T, Kato K, Takagi J. Structural basis for amyloidogenic peptide recognition by sorLA. Nat Struct Mol Biol. 2015 Mar;22(3):199-206. Epub 2015 Feb 2 PubMed.

Further Reading

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