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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

Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are...

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Autores principales: Huybrechts, Yentl, Boudin, Eveline, Hendrickx, Gretl, Steenackers, Ellen, Hamdy, Neveen, Mortier, Geert, Martínez Díaz-Guerra, Guillermo, Bracamonte, Milagros Sierra, Appelman-Dijkstra, Natasha M., Van Hul, Wim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774882/
https://www.ncbi.nlm.nih.gov/pubmed/35052419
http://dx.doi.org/10.3390/genes13010080
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author Huybrechts, Yentl
Boudin, Eveline
Hendrickx, Gretl
Steenackers, Ellen
Hamdy, Neveen
Mortier, Geert
Martínez Díaz-Guerra, Guillermo
Bracamonte, Milagros Sierra
Appelman-Dijkstra, Natasha M.
Van Hul, Wim
author_facet Huybrechts, Yentl
Boudin, Eveline
Hendrickx, Gretl
Steenackers, Ellen
Hamdy, Neveen
Mortier, Geert
Martínez Díaz-Guerra, Guillermo
Bracamonte, Milagros Sierra
Appelman-Dijkstra, Natasha M.
Van Hul, Wim
author_sort Huybrechts, Yentl
collection PubMed
description Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third β-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first β-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first β-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.
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spelling pubmed-87748822022-01-21 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 Mortier, Geert Martínez Díaz-Guerra, Guillermo Bracamonte, Milagros Sierra Appelman-Dijkstra, Natasha M. Van Hul, Wim Genes (Basel) Article Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third β-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first β-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first β-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder. MDPI 2021-12-28 /pmc/articles/PMC8774882/ /pubmed/35052419 http://dx.doi.org/10.3390/genes13010080 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huybrechts, Yentl
Boudin, Eveline
Hendrickx, Gretl
Steenackers, Ellen
Hamdy, Neveen
Mortier, Geert
Martínez Díaz-Guerra, Guillermo
Bracamonte, Milagros Sierra
Appelman-Dijkstra, Natasha M.
Van Hul, Wim
Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title_full Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title_fullStr Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title_full_unstemmed Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title_short Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis
title_sort identification of compound heterozygous variants in lrp4 demonstrates that a pathogenic variant outside the third β-propeller domain can cause sclerosteosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774882/
https://www.ncbi.nlm.nih.gov/pubmed/35052419
http://dx.doi.org/10.3390/genes13010080
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