Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis

Huybrechts, Yentl; Boudin, Eveline; Hendrickx, Gretl; Steenackers, Ellen; Hamdy, Neveen A. T.; Mortier, Geert; Díaz-Guerra, Guillermo Martínez; Bracamonte, Milagros Sierra; Appelman‐Dijkstra, Natasha M.; Hul, Wim Van

doi:10.3390/genes13010080

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…This variant is causal for sclerosteosis when present as heterozygous compound mutation together with another pathogenic variant in LRP4 (p.R1170Q). Cell-based assays confirmed how both of these mutations in LRP4 reduced receptor activity, providing support of the important function of the arginine also within the YWTD-domain of LRP4 [ 29 ]. We summarize these findings and literature in Table 3 .…”

Section: Resultsmentioning

confidence: 90%

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: Resultsmentioning

confidence: 90%

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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show abstract

“…In previous work 25 , we identified 5 pathogenic variants in homologous proteins corresponding to substitution of an arginine at the YWTD-blade sequence position 38: one in LDLR: p.R595W LDLR in Familial hypercholesterolemia (FHCL1) patients 35 ; three in LRP5: p.R494Q LRP5 in patients with Osteoporosis-pseudoglioma (OPPG) 36,37 ; p.R752G LRP5 in a family with Exudative Vitreoretinopathy (EVR4) 38 ; and p.R1188W LRP5 , a variant that segregates with disease in large family pedigrees with Polycystic Liver Disease 4 (PCLD4) 39 ; and one in LRP4: p.R632H LRP4 that is causal of sclerosteosis and shows impaired activity documented by functional assays 40 .…”

Section: Variant Characterizationmentioning

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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Mapping the sclerostin–LRP4 binding interface identifies critical interaction hotspots in loops 1 and 3 of sclerostin

Katchkovsky,

Meiri,

Lacham‐Hartman

et al. 2024

FEBS Letters

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The interaction of sclerostin (Scl) with the low‐density lipoprotein receptor‐related protein 4 (LRP4) leads to a marked reduction in bone formation by inhibiting the Wnt/β‐catenin pathway. To characterize the Scl–LRP4 binding interface, we sorted a combinatorial library of Scl variants and isolated variants with reduced affinity to LRP4. We identified Scl single‐mutation variants enriched during the sorting process and verified their reduction in affinity toward LRP4—a reduction that was not a result of changes in the variants' secondary structure or stability. We found that Scl positions K75 (loop 1) and V136 (loop 3) are critical hotspots for binding to LRP4. Our findings establish the foundation for targeting these hotspots for developing novel therapeutic strategies to promote bone formation.

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Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis

Cited by 4 publications

References 24 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

Mapping the sclerostin–LRP4 binding interface identifies critical interaction hotspots in loops 1 and 3 of sclerostin

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