Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr11:121481839 T>G
dbSNP ID: rs1472689639
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to TGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 39

Findings

The variant was found in none of 5198 Alzheimer's cases and one of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project, consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019).

Functional Consequences

Phenylalanine-1765 is located in the third 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). Andersen and colleagues have described phenylalanine-1765 as contributing to a “hydrophobic glue” that holds together the folds of the 3Fn domain, and they predicted that non-conservative substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023). The replacement of phenylalanine with cysteine, which is also hydropobic, might be tolerated.

Pathogenic variants were identified at homologous positions in three other proteins: the netrin receptor DCC, leading to mirror movements 1 (MRMV1); the interleukin receptor common gamma chain (IL2RG), causing X-linked severe combined immunodeficiency; and the growth hormone receptor, causing Laron syndrome (Andersen et al., 2023).

The F1765C variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Campion et al., 2019).

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References

Paper Citations

1. 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.
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