Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121619892 C>T
Position: (GRCh37/hg19):Chr11:121490601 C>T
dbSNP ID: rs778866380
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 43

Findings

In a pan-European cohort of 1255 Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, an Italian AD case was found to be a heterozygous carrier of this variant (Verheijen et al., 2016). The patient’s age of onset was 64 years and she had 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 P1955L variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Proline-1955 is located in the fifth of SORL1’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 proline-1955 are highly likely to increase AD risk (Andersen et al., 2023).

Pathogenic variants were identified at homologous positions in three other proteins: usherin, leading to retinitis pigmentosa 39; neural cell adhesion molecule L1 (L1CAM), causing mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome (MASA); and the insulin receptor, causing Rabson-Mendenhall syndrome (Andersen et al., 2023).

The 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. Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. 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.
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.

Further Reading

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