Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121614898 A>G
Position: (GRCh37/hg19):Chr11:121485607 A>G
dbSNP ID: rs772677709
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 41

Findings

Multiple lines of evidence—including cell-based studies of the effects of the mutation on protein function, pedigree analysis of families harboring the variant, and domain-mapping of disease mutations—suggest that the SORL1 Y1816C variant is pathogenic for Alzheimer's disease.

In cell-based assays, the variant prevented SORL1 maturation and dimerization in endosomes and trafficking of the protein to the plasma membrane, resulting in decreased shedding of soluble SORL1 (Jensen et al., 2023). SORL1 dimerization previously was shown to facilitate retromer-dependent APP recycling (Jensen et al., 2023; see Feb 2023 news). Together these findings suggest that the Y1816C variant will lead to increased amyloidogenic processing of APP. Moreover, the variant caused swelling of endosomes, a cytopathological characteristic of AD, in iPSC-derived human neurons.

The Y1816C variant has been reported in three unrelated families with a history of AD.

The Y1816C variant was first identified in an Italian family with three affected siblings (Verheijen et al., 2016; Jensen et al., 2023). The proband and an affected sibling (ages of onset 62 and 68 years, respectively; both APOE E3/E4) carried the variant; genotype information was not available from the third affected sibling. Another sibling (APOE E3/E4), unaffected at age 61, was a noncarrier. A child of the proband was reportedly diagnosed with Parkinson’s disease, with onset at 56 years.

In a Spanish pedigree, the proband (age of onset 59 years, APOE E3/E4), two of his four siblings (ages of onset 54 and 60 years), his father (age of onset 60 years), and a paternal aunt (age of onset 60 years) were diagnosed with probable AD. The proband was found to carry the SORL1 Y1816C variant but no pathogenic mutations in APP, PSEN1, or PSEN2. Of the proband’s four siblings, three also carried the Y1816C variant—the two affected sisters (both APOE E3/E4) and a sibling unaffected at 55 years of age (APOE E3/E3)—while the fourth, unaffected sibling (APOE E3/E4) did not carry the variant (Jensen et al., 2023).

Another carrier of Y1816C was found in a Dutch family with a pattern of inheritance consistent with autosomal dominant AD (Jensen et al., 2023). The proband began exhibiting signs at age 57 and received a clinical diagnosis of AD, supported by CSF biomarker findings, at age 61. She carried the SORL1 Y1816C variant but no pathogenic mutations in APP, PSEN1, or PSEN2, and her APOE genotype was E3/E4. One of the proband’s four siblings, her mother, maternal grandmother, two maternal uncles, a maternal aunt, and a cousin (daughter of the affected aunt) were reported to have dementia, with ages of onset ranging from approximately 60 to 69 years. Genotype information was not available from family members of the proband.

The Y1816C variant has also been reported in case-control studies. Five Alzheimer’s cases were identified as carriers of this variant among 8872 AD cases and 8970 controls from four non-overlapping datasets of subjects of European ancestry (the French Alzheimer’s Disease Exome Sequencing [ADESFR], Bellenguez et al., 2017; the Alzheimer’s Disease Sequencing Project [ADSP], Campion et al., 2019; a multicenter Dutch sample, Holstege et al., 2017; and the European Early-Onset Dementia Consortium [EOD], Verheijen et al, 2016). Among these five carriers were the proband from the Dutch family and the two carriers from the Italian family mentioned above. Subsequently, six carriers of this variant—all Alzheimer’s cases—were reported among 15,808 AD cases and 16,097 controls in a study that combined data from multiple European and American cohorts (Holstege et al., 2022). These carriers included the Dutch proband, four subjects from ADESFR, and a subject from ADSP, with ages of onset ranging from 44 to 75 years (Jensen et al., 2023).

Two carriers of the Y1816C variant were found among more than 125,000 individuals in the gnomAD database (v.2.1.1), which includes people with neurological diseases, but no carriers were found when the dataset was restricted to the nearly 115,000 people who were not participants in a neurologic or psychiatric case-control study (Jensen et al., 2023).

The Y1816C variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Tyrosine-1816 is located in the third 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—tyrosine is conserved at equivalent positions in all known 3Fn domains—Andersen and colleagues predicted that substitutions at tyrosine-1816 are highly likely to increase AD risk (Andersen et al., 2023). This prediction is bolstered by their domain mapping of disease-mutations analysis, which identified disease-associated tyrosine-to-cysteine substitutions at homologous positions in five other proteins.

The Y1816C variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 expressed in HEK293 cells (Rovelet-Lecrux et al., 2021; Jensen et al., 2023). Cleavage of SORL1 at the cell surface releases a soluble fragment (sSORL1), and less sSORL1 was found in the medium of cells expressing the Y1816C variant, compared with cells expressing the wild-type protein (Jensen et al., 2023). Consistent with these in vitro findings, lower levels of sSORL1 were found in the cerebrospinal fluid of the Dutch carrier of the Y1816C variant, compared with an unrelated AD case of the same age, gender, and APOE genotype who carried only wild-type SORL1 (Jensen et al., 2023).

Using fluorescently-tagged “minireceptors” (SORL1’s 3Fn cassette, transmembrane region, and cytoplasmic tail) or full-length SORL1 expressed in HEK293 cells, it was further shown that the Y1816C mutation impaired receptor dimerization and co-localization with retromer (Jensen et al., 2023).

Endosomal swelling occurred in iPSC-derived human neurons in which the Y1816C mutation was introduced by CRISPR/Cas9 gene editing prior to differentiation (Jensen et al., 2023).

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.

Comments

1. • Gael Nicolas
     Rouen University Hospital
   • Posted: 21 Jul 2023
   • Paper: The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease

   I think this variant is definitely a strong contributor to AD. However, the pedigrees also show that the patients with DNA available and carrying the variant also carry one APOE4 allele. Actually, APOE4 segregates as well as does SORL1 in these pedigrees. All affected individuals with DNA available are SORL1+/APOE4+. One unaffected individual is SORL1+/APOE4- (family 1) and one unaffected individual is SORL1-/APOE4+ (family 2). To be clear, I have absolutely no doubt of a major role of the SORL1 variant here, but I feel that this is very much consistent with a more complex inheritance and not purely autosomal-dominant, as shown in our penetrance paper (Schramm et al., 2022). Interestingly, we have the same variant in three independent families from France (one of them is mentioned in this preprint). Although there is an obvious aggregation of AD cases in the families, there is a huge diversity of ages of onset and younger cases have a positive family history in both branches, suggesting the contribution of additional factors. Some of them are APOE4+ but not the two youngest probands. This may suggest the contribution of undetected contributing variants along with SORL1.

   Overall, our penetrance paper (Schramm et al., 2022) and many pedigrees suggest a contribution of additional factors with SORL1 variants and that SORL1 alone may not be sufficient/fully penetrant. We have clear evidence for APOE4, as this is a common allele, but we know that there are many other other AD-associated variants, especially rare variants, among known variants (such as families with SORL1+ABCA7 as we previously reported in Campion et al., 2019), and in other papers and, obviously, not yet known variants.

   I thus recommend to use such results with great caution for genetic counseling, as we still don't exactly know how variants in other genes may drastically change an age of onset from 50 to 75-80 for example, or to absence of AD (as also shown for some truncating variants, as in Campion et al., 2019 where a mother transmitted a truncating a truncating variant and was unaffected with AD at age 95 years).

   References:

   Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.

   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.

   View all comments by Gael Nicolas

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References

News Citations

1. When SORL1 Dimerizes in Endosomes, Retromers Recycle APP Faster 1 Feb 2023

Paper Citations

1. Jensen AM, Raska J, Fojtik P, Monti G, Lunding M, Vochyanova S, Pospisilova V, vanderLee SJ, VanDongen J, Bossaerts L, VanBroeckhoven C, Dols O, Lleo A, Benussi L, Ghidoni R, Hulsman M, Sleegers K, Bohaciakova D, Holstege H, Andersen O. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. 2023 Jul 13 10.1101/2023.07.09.23292253 (version 1) medRxiv.
2. 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.
3. 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.
4. Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.
5. 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.
6. 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.
7. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
8. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.
9. 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.
10. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. PubMed.

Further Reading