Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121545399 A>G
Position: (GRCh37/hg19):Chr11:121416108 A>G
dbSNP ID: rs762176154
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 14

Findings

The N674S variant was identified in a family with nine Alzheimer’s patients in four generations (Louwersheimer et al., 2017). Pedigree analysis suggested an autosomal dominant pattern of inheritance, but no mutations in APP, PSEN1, or PSEN2 were found in this family. Rather, it appears that mutations in SORL1 or TSHZ3 (teashirt zinc finger homeobox 3) on a homozygous APOE E4 background may contribute to the expression of AD in this family.

DNA was available from four affected and seven non-affected family members. Of the affected subjects, three exhibited clinical symptoms of AD, with symptom onset ranging from 61 to 74 years, while the fourth presented at age 58 with subjective cognitive impairment and a biomarker profile suggestive of preclinical AD (low CSF Aβ42, elevated CSF total-tau and phospho-tau, and positive amyloid-PET). All four of the affected subjects were heterozygous for the N674S variant in SORL1 and homozygous for the E4 allele of APOE. The seven unaffected subjects ranged from 47 to 60 years of age, with no self-reported cognitive complaints. Of the seven, four carried the SORL1 N674S variant; the APOE genotypes of these four subjects are E3/E3, E3/E4, E3/E4, and E4/E4. Of the three unaffected subjects who did not carry the SORL1 N674S mutation, two were APOE E3/E4, and the third was E4/E4.

Notably, three of the affected subjects and one non-affected subject also carried a T236M mutation in the TSHZ3 gene. Two SNPs in TSHZ3 were reported to be associated with AD in a Caucasian cohort composed of 492 AD cases and 496 controls, and TSHZ3 was found to bind to FE65, an adapter protein that may have a role in APP trafficking and signaling by the APP intracellular domain (Kajiwara et al., 2009).

Fourteen additional variants were found in family members, including a frameshift in FUT1 and variants predicted to be damaging in DLD, ADARB2, and DRG2.

Two additional heterozygous carriers have been reported, an AD patient in a Dutch cohort of 640 Alzheimer’s cases and 1268 controls (Holstege et al., 2017) and a 63-year-old Belgian control subject in a study of 1255 AD cases and 1938 controls from the European Early Onset Dementia Consortium (Verheijen et al., 2016).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed once among the controls (Holstege et al., 2022).

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

Functional Consequences

Amino acid 674 is a highly conserved glycosylation site within the VPS10p domain of SORL1 (Louwersheimer et al., 2017). The arginine-to-serine substitution is predicted to be deleterious by PolyPhen-2 and Mutation Taster, but tolerated by SIFT (Verheijen et al., 2016; Louwersheimer et al., 2017).

In a study investigating the effects of SORL1 missense mutations on protein processing, the N674S variant did not affect the maturation (glycosylation) of SORL1 over expressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

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References

Paper Citations

1. Louwersheimer E, Cohn-Hokke PE, Pijnenburg YA, Weiss MM, Sistermans EA, Rozemuller AJ, Hulsman M, van Swieten JC, van Duijn CM, Barkhof F, Koene T, Scheltens P, Van der Flier WM, Holstege H. Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. J Alzheimers Dis. 2017;56(1):63-74. PubMed.
2. Kajiwara Y, Akram A, Katsel P, Haroutunian V, Schmeidler J, Beecham G, Haines JL, Pericak-Vance MA, Buxbaum JD. FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. PLoS One. 2009;4(4):e5071. 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. 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.
5. 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.
6. 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

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