Early-onset Alzheimer's disease may be associated with sortilin-related receptor 1 gene mutation: A family report and review

Zhu, Feiqi; Qiu, Guozhen

doi:10.1016/j.radcr.2020.10.030

Cited by 2 publications

(2 citation statements)

References 16 publications

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“…We have seen several publications reporting the identification of SORL1 variants that were not observed in our sample namely: R953C (Fazeli et al, 2023), R1303C (Thonberg et al, 2017), R1084C (El Bitar et al, 2019, C1192Y (Cao et al, 2021), C1344R (Thonberg et al, 2017), C1453S and C1249S (Verheijen et al, 2016).…”

Section: Discussionmentioning

confidence: 65%

Effect of prioritizedSORL1missense variants supports clinical consideration for familial Alzheimer’s Disease

Holstege,

de Waal,

Tesi

et al. 2023

Preprint

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Background:Rare variants in the SORL1 gene have been associated with increased risk of Alzheimer′s disease (AD). While protein−truncating variants (PTVs) are observed almost exclusively in AD patients, most variants are rare missense variants that can be benign, risk−increasing, and recent reports have indicated that some variants are causative for disease. However, since SORL1 is currently not considered an autosomal dominant Alzheimer Disease gene (ADAD), segregation analyses are not performed, which complicates the identification of additional clinically important missense variants.Methods:We prioritized highly conserved and functionally relevant SORL1 missense variants by considering the functional effects of homologous variants on proteins that share domains with SORL1 (domain-mapping of disease mutations, DMDM) into. We used this variant prioritization approach to annotate SORL1 variants identified in a previously assembled exome sequencing dataset encompassing 18,959 AD cases and 21,893 non-demented controls, and we tested the effect of high, moderate, low and no priority missense variants and specific variant subtypes on disease risk and age at onset.Results:High priority missense variants (HPV) associated with a 6.4−fold increased risk of AD (95%CI: 4.3 − 9.7, p=2.1×10−24), which concentrated on early onset AD (OREOAD 10.5, 95%CI: 6.8 − 16.3, p=3.0×10−29) vs. late onset AD (ORLOAD=4.5, 95%CI 2.85 − 6.94; p=4.9×10-11). The median age at onset of HPV carriers was >8−years earlier than carriers of wild-type SORL1. Intriguingly, specific subtypes of HPVs, including those affecting residues in the YWTD-motif or the calcium cage, occurred only in AD cases and carriers of these variants had an earlier age at onset compared to carriers of PTVs, indicative of a dominant negative effect. Carriers of other HPVs had an age at onset that overlapped with carriers of PTVs, suggesting they lead to haploinsufficiency. Yet other variants had a slightly later age at onset than PTVs, suggesting that their effect on SORL1 function was milder than losing a copy. Variants annotated as moderate, low and no priority did not have an effect on AD.Conclusions:Next to carriers of SORL1 PTVs, carriers of selected missense variants should be considered for segregation analyses, which will likely provide evidence for autosomal dominant inheritance for additional SORL1 missense variants.

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Section: Discussionmentioning

confidence: 65%

Effect of prioritizedSORL1missense variants supports clinical consideration for familial Alzheimer’s Disease

Holstege,

de Waal,

Tesi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Both variants resulted in CR-domains with 7 Cys residues. Also, a 59-year-old AD patient who carried a variant leading to p.C1192Y was reported 38 , this variant results in the third CR-domain having 5 Cys residues. Furthermore, variants leading to p.C1344R was reported to associate with a possible family history in a Finnish family 33 , as well as the p.C1453S and p.C1249S variants were reported for AD patients only 9 .…”

Section: Cr-cluster (Residues 1075-1550)mentioning

confidence: 99%

Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity ofSORL1variants in Alzheimer’s disease

Andersen

Monti

Jensen

et al. 2023

Preprint

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SORL1 encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer's disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Here we address this question by relying on SORLA's distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive compendium on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations. We envision that this compendium will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Utimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients.

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Early-onset Alzheimer's disease may be associated with sortilin-related receptor 1 gene mutation: A family report and review

Cited by 2 publications

References 16 publications

Effect of prioritizedSORL1missense variants supports clinical consideration for familial Alzheimer’s Disease

Effect of prioritizedSORL1missense variants supports clinical consideration for familial Alzheimer’s Disease

Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity ofSORL1variants in Alzheimer’s disease

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