Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121591052 A>G
Position: (GRCh37/hg19):Chr11:121461761 A>G
dbSNP ID: rs200889461
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to AGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 31

Findings

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 four times among the AD cases (Holstege et al., 2022).

Previously, this variant was reported in cohorts from the Alzheimer Disease Exome Sequencing France project (ADESFR) and the Alzheimer’s Disease Sequencing Project (ADSP), both of which contributed data to the 2022 study cited above: An early onset AD case was found to be a heterozygous carrier of this variant in a group of 1273 controls, 927 late-onset AD, and 852 early onset AD cases from ADESFR (Bellenguez et al., 2017; Campion et al., 2019) and another early onset case was reported among 5198 AD cases and 4491 controls from ADSP (Campion et al., 2019).

A French carrier of the variant, an early onset AD patient, has been described in detail (Le Guennec et al., 2018). This patient was found to carry three SORL1 variants, including two protein-truncating variants in trans, expected to cause a bi-allelic loss of function of SORL1. The proband (APOE E3/E4) was 55 years old at dementia onset. He inherited the protein-truncating splice-site variant g.121459965 insG (c.3947-3insG) and the g.121461761 A>G variant (causing an arginine-to-serine substitution at amino acid 1422) from his mother (APOE E3/E3), who was demented prior to age 78. As the g.121459965 insG mutation occurs upstream of g.121461761 A>G , it is unlikely that SORL1 N1422S is expressed in this carrier. The third variant, the protein-truncating splice-site variant g.121385032 T>G (c.1211+2T>G), was inherited from his father, who also suffered from dementia, with onset prior to age 70. The proband’s paternal grandfather was demented by 65 years of age, while his maternal grandparents each died before age 65, without a known dementia diagnosis.

Functional Consequences

The N1422S variant was predicted to be tolerated by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2. In addition, splicing prediction software indicated that this variant might introduce a novel 3’ splice site, leading to a loss of 52 base pairs and a frameshift (Le Guennec et al., 2018).

In a study investigating the effects of SORL1 missense mutations on protein processing, the N1422S variant did not affect the maturation (glycosylation) of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. 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.
2. 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.
3. 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.
4. Le Guennec K, Tubeuf H, Hannequin D, Wallon D, Quenez O, Rousseau S, Richard AC, Deleuze JF, Boland A, Frebourg T, Gaildrat P, Campion D, Martins A, Nicolas G. Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. J Alzheimers Dis. 2018;62(2):821-831. PubMed.
5. 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