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Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy

Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic va...

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Autores principales: Yan, Wenjin, Zheng, Liming, Xu, Xingquan, Hao, Zheng, Zhang, Yibo, Lu, Jun, Sun, Ziying, Dai, Jin, Shi, Dongquan, Guo, Baosheng, Jiang, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477389/
https://www.ncbi.nlm.nih.gov/pubmed/36067312
http://dx.doi.org/10.1073/pnas.2203557119
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author Yan, Wenjin
Zheng, Liming
Xu, Xingquan
Hao, Zheng
Zhang, Yibo
Lu, Jun
Sun, Ziying
Dai, Jin
Shi, Dongquan
Guo, Baosheng
Jiang, Qing
author_facet Yan, Wenjin
Zheng, Liming
Xu, Xingquan
Hao, Zheng
Zhang, Yibo
Lu, Jun
Sun, Ziying
Dai, Jin
Shi, Dongquan
Guo, Baosheng
Jiang, Qing
author_sort Yan, Wenjin
collection PubMed
description Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1(+/−)) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1(R1783W)) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant β-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a β-catenin antagonist) in an shRNA-Lrp1–expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.
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spelling pubmed-94773892022-09-16 Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy Yan, Wenjin Zheng, Liming Xu, Xingquan Hao, Zheng Zhang, Yibo Lu, Jun Sun, Ziying Dai, Jin Shi, Dongquan Guo, Baosheng Jiang, Qing Proc Natl Acad Sci U S A Biological Sciences Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1(+/−)) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1(R1783W)) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant β-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a β-catenin antagonist) in an shRNA-Lrp1–expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment. National Academy of Sciences 2022-09-06 2022-09-13 /pmc/articles/PMC9477389/ /pubmed/36067312 http://dx.doi.org/10.1073/pnas.2203557119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Yan, Wenjin
Zheng, Liming
Xu, Xingquan
Hao, Zheng
Zhang, Yibo
Lu, Jun
Sun, Ziying
Dai, Jin
Shi, Dongquan
Guo, Baosheng
Jiang, Qing
Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title_full Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title_fullStr Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title_full_unstemmed Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title_short Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
title_sort heterozygous lrp1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477389/
https://www.ncbi.nlm.nih.gov/pubmed/36067312
http://dx.doi.org/10.1073/pnas.2203557119
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