Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121627591 C>T
Position: (GRCh37/hg19):Chr11:121498300 C>T
dbSNP ID: rs142884576
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 47

Findings

This variant was found in a family in which a parent and four offspring suffered from Alzheimer’s disease, with ages of onset ranging from 55 to 84 years (Cuccaro et al., 2016). Genotype data were available from the four affected siblings and one sibling unaffected at age 79. Three of the four affected individuals were heterozygous for the T2134 variant, as was the unaffected sibling; the remaining affected sibling was a non-carrier. (All of the T2134M carriers were homozygous for the E3 allele of APOE, while the affected non-carrier was E3/E4.) Thus, the T2134 variant did not segregate with disease in this family. (Note: The three affected carriers in this family were also reported in (Kunkle et al., 2017)).

No additional carriers were found in another 22 families of European ancestry selected for their high burdens of AD (average of eight affected members per family) (Cukier et al., 2017).

The T2134M variant was also reported in several case-control studies (see table). The variant did not associate with AD in a mega-analysis of nearly 32,000 subjects drawn from multiple European and American datasets (Holstege et al., 2022).

The T2134M variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Residue 2134 is located within the stalk region, a 16-amino acid stretch (amino acids 2122-212137) that acts as a spacer between the plasma membrane and SORL1’s ectomain (Andersen et al., 2023).

The T2134M mutation appears to reduce trafficking of SORL1 to the cell surface and, once there, to disrupt its binding to APP (Cuccaro et al., 2016). Cells transfected with T2134 and wild-type SORL1 expressed similar levels of total SORL1 protein, but there was only about 25 percent of the mutant protein at the cell surface, compared with the wild-type protein. The mutation also caused an approximately 60 percent reduction in the amount of APP bound to SORL1, which was accompanied by increased amounts of APP at the cell surface. HEK293 cells transfected with this variant secreted more Aβ40 (167%), Aβ42 (117%), sAPPα (223%), and sAPPβ (140%) into the culture medium than did cells transfected with wild-type SORL1.

In a study investigating the effects of SORL1 missense mutations on protein processing, the T2134M variant did not affect the maturation (glycosylation) of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

The T214M variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Campion et al., 2019).

Table

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Cuccaro ML, Carney RM, Zhang Y, Bohm C, Kunkle BW, Vardarajan BN, Whitehead PL, Cukier HN, Mayeux R, St George-Hyslop P, Pericak-Vance MA. SORL1 mutations in early- and late-onset Alzheimer disease. Neurol Genet. 2016 Dec;2(6):e116. Epub 2016 Oct 26 PubMed.
2. Kunkle BW, Vardarajan BN, Naj AC, Whitehead PL, Rolati S, Slifer S, Carney RM, Cuccaro ML, Vance JM, Gilbert JR, Wang LS, Farrer LA, Reitz C, Haines JL, Beecham GW, Martin ER, Schellenberg GD, Mayeux RP, Pericak-Vance MA. Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport. JAMA Neurol. 2017 Sep 1;74(9):1113-1122. PubMed.
3. Cukier HN, Kunkle BK, Hamilton KL, Rolati S, Kohli MA, Whitehead PL, Jaworski J, Vance JM, Cuccaro ML, Carney RM, Gilbert JR, Farrer LA, Martin ER, Beecham GW, Haines JL, Pericak-Vance MA. Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. J Alzheimers Dis Parkinsonism. 2017 Aug;7(4) Epub 2017 Jul 31 PubMed.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.
10. 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.
11. 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.
12. 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

No Available Further Reading