Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558784 C>T
Position: (GRCh37/hg19):Chr11:121429493 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 20

Findings

The R953C variant was identified in a family seen at the University of Washington Alzheimer Disease Research Center in which neurological disorders occurred in eight family members across three generations (Fazeli et al., 2023).

The proband underwent genetic testing for APP and PSEN1 mutations due to early age of onset (51 years) and family history, but no mutations in these genes were found. After his death, his sample was included in an exome-sequencing study that screened for variants in 27 genes associated with dementia risk—including APP, PSEN1, PSEN2, MAPT, FUS, GRN, and SORL1—in people with early onset AD, and the SORL1 R953C variant was identified.

Subsequently, exome sequencing of affected siblings of the proband—his twin brother (age of onset 57 years), and two sisters (ages of onset 53 and 73 years)—revealed that all three carried the SORL1 R953C variant, but no other likely pathogenic variants in dementia-associated genes. These siblings were clinically diagnosed with Alzheimer’s disease, and their diagnoses were neuropathologically confirmed after their deaths. A fifth sibling, genotype unknown, was clinically diagnosed with probable AD (age of onset in her late 60s). Their mother, with autopsy-confirmed AD (age of onset 78 years) did not carry the SORL1 variant. Their father, genotype unknown, was diagnosed with “severe dementia” of unspecified type, with Parkinsonism and aggressive behavior noted. Finally, a 46-year-old niece of the proband, also found to carry the R953C variant, suffers from spastic paraplegia. All of the genotyped individuals in the second and third generations were APOE E3/E3.

Another variant at this position, R953H, was found in three early onset AD cases (Holstege et al., 2022; Andersen et al., 2023).

Neuropathology

AD pathology—amyloid plaques and neurofibrillary tangles—was present in the brains of the four siblings who came to autopsy, as well as their mother. Notably, all of the siblings, who carried the R953C variant, had TDP-43 inclusions in the amygdala and hippocampus. TDP-43 pathology was not seen in the mother, who did not carry the variant. Lewy body pathology was observed in the brains of two of the sibling R953C carriers.

Functional Consequences

Arginine-953 is located in the fifth of the six “blades” that form SORL1’s YWTD β-propeller domain. Structural modeling of SORL1 and analysis of the crystal structures of homologous domains in LDLR, LRP4, and LRP6 suggest that arginine-953 is critical for the folding and stability of the β-propeller domain (Fazeli et al., 2023).

Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of arginine-953 are highly likely to increase the risk of Alzheimer’s disease (Andersen et al., 2023; Fazeli et al., 2023). Five pathogenic variants were identified in homologous positions in three other proteins: a variant in LDLR linked to familial hypercholesterolemia 1; variants in LRP5 that were found in patients with osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy 4, or polycystic liver disease 4; and a variant in LRP4 believed to cause sclerosteosis.

The R953C mutation impaired maturation (glycosylation) and disrupted trafficking of SORL1 expressed in HEK293 or N2a cells (Fazeli et al., 2023). R953C SORL1 was sequestered in the endoplasmic reticulum and failed to reach the cell surface—preventing shedding of soluble SORL1—or enter endosomal compartments.

Comments

1. • Gael Nicolas
     Rouen University Hospital
   • Posted: 22 Jul 2023
   • Paper: A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting.

   This is another example of a missense variant affecting shedding and maturation of SORL1 in a family, segregating incompletely with AD, and with large diversity of ages of onset. Such diversity, and putative inheritance from the father with dementia at the age of 83, suggests that additional factors may be required to result in AD, at least before the age of 70-75, knowing that LOAD is very common. In my opinion, this variant may be insufficient to cause AD, although it seems to be a strong determinant.

   We also have the same variant as in this work, in one of our unpublished patients (R953C). It is a sporadic case with an age at onset of 56 years, APOE genotype 3/4, unaffected parents at 80, large family, no other case except a paternal grandmother with an age at onset of 80. Unless there is a de novo mutation, which we could not check yet, it is inconsistent with autosomal-dominant inheritance. I hope we can see if one of the parents is a carrier, as this will help us better understand the variant's penetrance.

   This paper adds another variant to the increasing list of variants with a maturation defect. We reported 15 variants with a similar effect in Rovelet-Lecrux et al., 2021 after expression of 70 missense variants in HEK cells. We selected three variants with such an effect, and two without, to further evaluate them in IPSCs after Crispr/cas9 introduction. We found that all three selected missense variants showed a maturation defect, including one with a milder effect. The two variants with the strongest maturation defect showed significantly increased secreted Aβ levels, clearly linking these variants to AD pathophysiology.

   It is, however, unclear why, in the current paper, the authors mention our own paper with the following sentence: "Furthermore, a larger screen of 70 SORL1 coding variants suggested that impaired maturation may be general for dysfunctional proteins although no correlation to AD was established." We only studied SORL1, and we showed a direct link with AD for these specific variants, with the above-mentioned mechanism. We discussed that maturation defect of the encoded protein by a missense variant is a known mechanism for other diseases, but here we studied SORL1 missense variants impairing the maturation of SORL1 protein (this resulting to increased secreted Aβ) and not any other protein. There must be a misunderstanding on this point.

   References:

   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.

   View all comments by Gael Nicolas

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. SORL1 R953H

Paper Citations

1. Fazeli E, Child DD, Bucks SA, Stovarsky M, Edwards G, Yu C-E, Latimer C, Kitago Y, Bird T, Andersen O, Jayadev S, Young JE. A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting. 2023 Jul 05 10.1101/2023.07.01.547348 (version 2) bioRxiv.
2. 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.
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