Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121570183 C>T
Position: (GRCh37/hg19):Chr11:121440892 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 23

Findings

This variant was discovered in a Saudi Arabian family with a history of early onset Alzheimer’s disease (El Bitar et al., 2019). The proband (age of onset 65 years; APOE genotype E3/E4), an affected brother (age of onset 63 years), and her unaffected 21-year-old son were heterozygous carriers of the variant. DNA was not available from two other affected family members, who were deceased—the proband’s mother (age of onset 49 years) and brother (age of onset 56 years)—or from her unaffected sister (age unspecified).

The proband was described as exhibiting memory impairments, declining cognition, and brain atrophy. Generalized atherosclerosis, diabetes, and high blood pressure were also present.

The variant was not found in the ExAC, 1000 Genomes, or Saudi Human Genome Program databases at the time of publication (El Bitar et al., 2019).

Subsequently, 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).

The variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Arginine-1084 is found in the first of SORL1’s 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Each CR contains six conserved cysteines. Variants resulting in an odd number of cysteines—either through substitution of one of these six cysteines or mutation of another residue to cysteine, as in the R1084C variant—may disrupt disulfide bridging. Based on domain mapping of disease mutations, Andersen and colleagues predicted that variants containing an odd number of cysteines in a CR domain (ONC variants) are highly likely to increase AD risk (Andersen et al., 2023): Approximately 40 percent of variants in LDLR linked to familial hypercholesterolemia are ONC variants, and ONC variants in LDL receptor related proteins 4 and 5 (LRP4 and LRP5) have been linked to Cenani–Lenz syndactyly syndrome and exudative vitreoretinopathy 4, respectively. Indeed, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 ONC variants significantly increased the risk of AD (OR = 6.31, 95% CI: 2.45 -16.24, p=5.1x10^-6; Fisher Exact test) (Andersen et al., 2023).

Arginine-1084 is a highly conserved residue in SORL1. Structural modeling suggested that the arginine-to-cysteine substitution causes changes in secondary structure and misfolding of the protein (El Bitar et al., 2019). In this model, the wild-type protein showed a coiled structure in the region between amino acids 1079 and 1235, with two beta sheets and two alpha helices. In the R1084C variant, there was a loss of beta-sheet structure and shortening of the alpha helices which flank the variant.

The R1084C variant was predicted to be deleterious by several algorithms: SIFT (damaging), Mutation Taster (disease-causing), PolyPhen-2 (probably damaging), PROVEAN (deleterious), and CADD (CADD/PHRED score of 35) (El Bitar et al., 2019).

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References

Paper Citations

1. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.
2. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 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