Mutations

SORL1 Y2059C

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121625089 A>G
Position: (GRCh37/hg19):Chr11:121495798 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 46

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 once among the controls (Holstege et al., 2022).

Functional Consequences

Tyrosine-2059 is located in the sixth of SORLA’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). Based on sequence conservation, Andersen and colleagues have predicted that substitutions at tyrosine-2059 are highly likely to increase AD risk (Andersen et al., 2023).

Pathogenic variants were identified at homologous positions in the insulin-like growth factor 1 receptor (IGR1R) and roundabout homolog 4, associated with insulin-like growth factor 1 resistance and aortic valve disease-3, respectively (Andersen et al., 2023).

Last Updated: 25 Jul 2023

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References

Paper Citations

  1. . 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. . 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. . 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

Protein Diagram

Primary Papers

  1. . 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. . 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.

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