Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer’s Disease Patients: Clinical, Neuroimaging and Neuropathological Findings

Álvarez-Mora, María Isabel; Blanco-Palmero, Víctor Antonio; Quesada‐Espinosa, Juan Francisco; Arteche‐López, Ana; Llamas‐Velasco, Sara; Milla, Carmen Palma; Rosales, Jose Miguel Lezana; Gómez-Manjón, Irene; Hernández-Laín, Aurelio; Almonacid, Justino Jiménez; Gil-Fournier, Belén; Ramiro-León, Soraya; González-Sánchez, Marta; Martín, Alejandro Octavio Herrero-San; Pérez-Martínez, D A; Gómez‐Tortosa, Estrella; Carro, Eva; Gómez-Rodriguez, Maria José; Sánchez-Calvín, María Teresa; Villarejo-Galende, Alberto; Moreno-Garcı́a, Marta

doi:10.3390/ijms23084230

Cited by 7 publications

(3 citation statements)

References 43 publications

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“…There are very few studies of neuropathology on SORL1 variant carriers. There is one report of a SORL1 homozygous truncating variant (c.364C > T, p.R122*) that shows severe cerebral amyloid angiopathy in addition to AD neuropathology as well as a patient with a splicing variant (c.4519 + 5G > A) in which AD was confirmed by neuropathological studies [ 5 ]. Yet another study shows SORL1 immunoreactivity in glial cells and white matter in a family with an SORL1 variant c.3907C > T, p. R1303C [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

A familial missense variant in the Alzheimer’s disease gene SORL1 impairs its maturation and endosomal sorting

Fazeli,

Child,

Bucks

et al. 2024

Acta Neuropathol

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The SORL1 gene has recently emerged as a strong Alzheimer’s Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

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Section: Discussionmentioning

confidence: 99%

A familial missense variant in the Alzheimer’s disease gene SORL1 impairs its maturation and endosomal sorting

Fazeli,

Child,

Bucks

et al. 2024

Acta Neuropathol

View full text Add to dashboard Cite

show abstract

“…There are very few studies of neuropathology on SORL1 variant carriers. There is one report of a SORL1 homozygous truncating variant (c.364C>T, p.R122*) that shows severe cerebral amyloid angiopathy in addition to AD neuropathology as well as a patient with a splicing variant (c.4519+5G>A) in which AD was confirmed by neuropathological studies [5]. Yet another study shows SORL1 immunoreactivity in glial cells and white matter in a family with a SORL1 variant c.3907C>T, p. R1303C.…”

Section: Discussionmentioning

confidence: 99%

A familial missense variant in the Alzheimer’s Disease geneSORL1impairs its maturation and endosomal sorting

Fazeli,

Child,

Bucks

et al. 2023

Preprint

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The SORL1 gene has recently emerged as a strong Alzheimer Disease risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still unknown. Here, we describe a multi-generational family with both early- and late-onset AD in two generations. Exome sequencing identified a coding variant, p.(Arg953Cys), in SORL1 in 4 of 5 individuals affected by AD. Notably, variant carriers had severe AD pathology, including the presence of Ab plaques in the cerebellum as well as TDP-43 pathology. We further characterized this variant and show that this Arginine substitution occurs at a critical domain position of the SORL1 translation product, SORL1. In vitro studies further show that the SORL1 p.R953C variant has decreased maturation and shedding of the SORL1 protein, and also leads to mis-localization within cells. Together, our analysis suggests that p.R953C is a likely pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

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“…The strongest genetic link to AD occurs for the SORL1 gene that has been included in the exclusive list of genes that can act as causal for AD (together with PSEN1, PSEN2, and APP [2]). Initially found in LOAD cohorts [83,[158][159][160][161][162][163][164], rare SORL1 variants were recently identified also in EOAD patients [85][86][87][165][166][167][168][169], and in cases with familial AD [85,170,171]. Its protein product, sorting-related receptor with A-type repeats (SorLA, also known as LR11), is the largest member of the VPS10p-D receptor family.…”

Section: Sorla Biology and Its Role In Admentioning

confidence: 99%

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

Salašová

Monti

Andersen

et al. 2022

Mol Neurodegeneration

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The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer’s disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.

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Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer’s Disease Patients: Clinical, Neuroimaging and Neuropathological Findings

Cited by 7 publications

References 43 publications

A familial missense variant in the Alzheimer’s disease gene SORL1 impairs its maturation and endosomal sorting

A familial missense variant in the Alzheimer’s disease gene SORL1 impairs its maturation and endosomal sorting

A familial missense variant in the Alzheimer’s Disease geneSORL1impairs its maturation and endosomal sorting

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

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