Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121591102 G>A
Position: (GRCh37/hg19):Chr11:121461811 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to AAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 31

Findings

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

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster, and ligand binding is Ca²⁺-dependent. In proteins with CR domains, each CR contains four amino acids whose acidic side chains, together with the backbone carbonyls of two additional residues, form an octahedral Ca²⁺ cage critical for proper folding of the domain. Residue 1439 is a component of the Ca²⁺ cage in CR9.

Andersen and colleagues predicted that variants affecting residues that contribute their acidic side chains to the Ca²⁺ cages are highly likely to increase AD risk (Andersen et al., 2023). Domain mapping of disease mutations revealed that several variants associated with medical conditions—in genes including LDLR (familial hypercholesterolemia), LRP2 (intellectual disability, Stickler syndrome), LRP5 (exudative vitreoretinopathy 4), TMPRSS3 (deafness), and TMPRSS6 (iron-refractory iron deficiency anemia)—occur in Ca²⁺-cage residues. Furthermore, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 Ca²⁺-cage variants significantly increased the risk of AD (OR = infinity), leading to the suggestion that these variants be considered causative for AD (Andersen et al., 2023).

The following Ca²⁺-cage variants are listed in the Alzforum database: D1108N, D1182N, D1219G, D1261G, D1267N, D1267E, D1345N, D1439N, D1502G, D1535N, D1545N, D1545G, D1545E. With the exception of D1267E, all carriers of these variants were Alzheimer’s cases.

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References

Paper Citations

1. 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