Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121615037 G>T
Position: (GRCh37/hg19):Chr11:121485746 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TGG to TGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 41

Findings

The W1862C variant was found in one of 1383 Alzheimer’s cases from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ), the French national reference center for young Alzheimer patients (Rovelet-Lecrux et al., 2021).

Subsequently, in a study that included 18,959 Alzheimer’s cases and 21,893 control subjects from multiple European and American cohorts, including CNR-MAJ, this allele was observed once among the AD cases (Henne Holstege, personal communication).

Functional Consequences

Tryptophan-1862 is located in the fourth of SORL1’s six 3Fn domains—named for fibronectin, the protein in which homologous domains were first described. SORL1’s 3Fn-cassette mediates receptor dimerization, which facilitates retromer-dependent transport of cargo out of endosomes (Jensen et al., 2023). Both sequence conservation and domain mapping of disease mutations led Andersen and colleagues to predict that substitutions of tryptophan-1862 are highly likely to increase AD risk (Andersen et al., 2023).

The W1862C variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

This variant was predicted to be damaging by SIFT, Mutation Taster, and PolyPhen-2 (Rovelet-Lecrux et al., 2021).

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References

Paper Citations

1. 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.
2. Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212180120. Epub 2023 Jan 18 PubMed.
3. 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.

Further Reading

No Available Further Reading