Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121545338 C>T
Position: (GRCh37/hg19):Chr11:121416047 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 14

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including the CNR-MAJ and ADESFR cohorts cited below, this allele was observed twice among the AD cases (Holstege et al., 2022).

This variant was initially reported in an Alzheimer’s patient in a French cohort composed of 484 early onset Alzheimer’s cases enrolled in the French National Reference Center for Young Alzheimer Patients (Centre National de Référence - Malades Alzheimer Jeunes, CNR-MAJ) and 498 controls (Nicolas et al., 2016). No additional carriers were found when the French dataset was expanded to include 927 late-onset AD cases, 852 early onset cases, and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Campion et al., 2019).

Subsequently, additional French carriers have been identified in three families in the CNR-MAJ dataset (Schramm et al., 2022). In the first family, in which five of 11 siblings were afflicted with Alzheimer’s disease, the variant did not segregate with disease: Among three affected siblings from whom genotype information is available, one carries the variant (age of onset 70 years; APOE E2/E3), while the other two do not (ages of onset 64 and 75 years, both APOE E3/E3). Another sibling, unaffected at age 68 (APOE E3/E3), is a noncarrier. Genotype information was not available from the other seven siblings. In the second family, the proband (age of onset 58 years, APOE E4/E4), an affected sibling (age of onset 67 years, APOE E3/E3), and a sibling unaffected at age 66 (APOE E4/E4) all carry this variant. Genotype information was not available from two other siblings, unaffected at ages 63 and 68 years, nor from the affected parent and grandparent of the proband (ages of onset 72 and 75 years, respectively). In the third family, the carrier (age of onset 66 years; APOE E3/E4) and an aunt or uncle (age of onset 65 years) were diagnosed with AD. Genotype information was available only from the proband.

The R654W variant was among 54 selected for genotyping in a North American cohort of 217 early onset AD cases and 169 controls. The variant was not found in this cohort. Nor was it found by whole- exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study (Fernández et al., 2016).

Functional Consequences

The R654W variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021). Defects in SORL1 maturation and cell-surface expression—with retention of the protein in the endoplasmic reticulum—were also observed when the variant was introduced into the endogenous SORL1 gene in human IPSCs. These changes in SORL1 localization were accompanied by increased release of Aβ.

The variant was predicted to be damaging by three algorithms: PolyPhen-2, Mutation Taster, and SIFT (Fernández et al., 2016).

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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. 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. 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. 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.
5. 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.
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.

Further Reading

No Available Further Reading