Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121627711 A>G
Position: (GRCh37/hg19):Chr11:121498420 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to AGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 47

Findings

In a pan-European cohort of 1255 Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, one Spanish AD case was found to be a heterozygous carrier of this variant (Verheijen et al., 2016). The carrier was 57 years old at disease onset, and she did not have a family history of AD.

No additional carriers were found among 5198 AD cases and 4491 controls from the Alzheimer’s Disease Sequencing Project from whom whole-exome sequencing data were available, 1779 AD cases and 1273 controls from the Alzheimer Disease Exome Sequencing France project, 332 cases and 676 controls of European ancestry from the United Kingdom and North America (Campion et al., 2019), or 640 cases and 1268 controls from a multi-center Dutch sample (Holstege et al., 2017).

The N2174S variant is classified as “uncertain: possibly pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Asparagine-2174 is located in SORL1’s cytoplasmic tail, within the ²¹⁷²FANSHY²¹⁷⁷ motif, a strictly conserved sequence necessary for binding the retromer complex (Fjorback et al., 2012). Andersen and colleagues have predicted that substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023).

Data on the functional consequences of substitutions at this specific residue are lacking. However, in vivo and in vitro studies showed that when the FANSHY domain was mutated to disrupt retromer binding, SORL1 accumulated in endosomes and was depleted from the Golgi/trans-Golgi network, while levels of APP cleavage products Aβ40, Aβ42, sAPPα, and sAPPβ increased (Fjorback et al., 2012; Dumanis et al., 2015). These findings can be explained if retromer-dependent sorting of SORL1 and its ligand APP from endosomes back to the Golgi/trans-Golgi network protects APP from processing in endosomal compartments.

This variant was predicted to be damaging by SIFT, disease causing by Mutation Taster, and probably damaging by PolyPhen-2 (Verheijen et al., 2016).

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References

Paper Citations

1. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
2. 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.
3. 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.
4. Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR, Willnow TE, Christensen EI, Mobley WB, Nykjaer A, Andersen OM. Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. PubMed.
5. 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.
6. Dumanis SB, Burgert T, Caglayan S, Füchtbauer A, Füchtbauer EM, Schmidt V, Willnow TE. Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain. J Neurosci. 2015 Sep 16;35(37):12703-13. PubMed.

Further Reading

No Available Further Reading