Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121496918 G>A
Position: (GRCh37/hg19):Chr11:121367627 G>A
dbSNP ID: rs117260922
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 6

Findings

The E270K variant was detected in North American (Fernández et al., 2016; Sassi et al., 2016), European (Gómez-Tortosa et al., 2018; Sassi et al., 2016; Verheijen et al., 2016), Saudi Arabian (El Bitar et al., 2019), and Caribbean Hispanic (Vardarajan et al., 2015) cohorts. Although one study reported a nominal association of the variant with the risk of early onset AD in European Americans (Fernández et al., 2016), two other studies found no association with the risk of AD in European or North Americans cohorts (Sassi et al., 2016; Verheijen et al., 2016). A meta-analysis of five studies including more than 18,000 subjects of European or European American ancestry did not show an association between the E270K variant and AD (Campion et al., 2019), nor did a mega-analysis of multiple European and American datasets totaling nearly 32,000 subjects (Holstege et al., 2022). The lack of association persisted when the latter dataset was expanded to more than 40,000 subjects (Holstege et al., 2023).

In a Spanish family with four affected members in two generations, the E270K variant did not segregate with disease: Of the three family members for whom genotype data were available, one affected (age of onset 64 years) and one unaffected (age 77) sibling were heterozygous carriers of the variant, while another affected (age of onset 74 years) sibling was a noncarrier (Gómez-Tortosa et al., 2018). However, in a study of Caribbean-Hispanic families with a family history of AD, this variant was found to segregate with disease under a dominant affecteds-only model (Vardarajan et al., 2015).

This variant is classified “uncertain: most likely not pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017; Gómez-Tortosa et al., 2018).

Functional Consequences

The biological effects of the E270K variant have been studied in HEK293 cells co-transfected with APP with the AD-linked Swedish mutation and either wild-type or mutant SORL1 (Vardarajan et al., 2015). The E270K variant resulted in increased levels of APP at the cell surface and increased secretion of Aβ40, Aβ42, sAPPα, and sAPPβ, compared with wild-type SORL1. The variant also showed reduced binding affinity to APP. Together these observations suggest that the E270K variant is less efficient than wild-type SORL1 at directing APP into the retromer-recycling endosome pathway.

Results consistent with the findings in HEK293 cells were seen in human neurons derived from iPSCs in which CRISPR/Cas9 gene editing was used to introduce the E270K mutation (Mishra et al., 2022). Levels of SORL1 protein were similar in neurons derived from the parental cell line and neurons heterozygous for the E270K variant. Neurons carrying the variant had enlarged early endosomes and increased levels of secreted Aβ40 and Aβ42, compared with those derived from the parental line, but these effects were not as extreme as those seen in isogenic SORL1-knockout iPSC-derived neurons. Treatment of cells expressing E270K with a small molecule that stabilizes retromer restored endosome size and reduced levels of Aβ. It should be noted that the parental cell line is homozygous for three SNPs (rs668387, rs689021, and rs641120) in linkage disequilibrium within intron 6 of SORL1—a haplotype reported to associate with an increased risk of AD (Rogaeva et al., 2007)—and that the APOE genotype is E3/E4 (Young et al., 2015; Knupp et al., 2020).

The variant was predicted to be disease-causing by Mutation Taster, probably damaging by PolyPhen-2, damaging by SIFT, and neutral by PROVEAN (El Bitar et al., 2019).

Table

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.
^bAddtional subjects added to the dataset reported by Holstege et al., 2022.
^cLinkage and association analysis with PSEUDOMARKER20 using all family members and unrelated controls.

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References

Paper Citations

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