CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage

Desbuquois dysplasia (DD) type 1 is a rare skeletal dysplasia characterized by a short stature, round face, progressive scoliosis, and joint laxity. The causative gene has been identified as calcium‐activated nucleotidase 1 (CANT1), which encodes a nucleotidase that preferentially hydrolyzes UDP to...

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Autores principales: Kodama, Kazuki, Takahashi, Hiroaki, Oiji, Nobuyasu, Nakano, Kenta, Okamura, Tadashi, Niimi, Kimie, Takahashi, Eiki, Guo, Long, Ikegawa, Shiro, Furuichi, Tatsuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262921/
https://www.ncbi.nlm.nih.gov/pubmed/32277574
http://dx.doi.org/10.1002/2211-5463.12859
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author Kodama, Kazuki
Takahashi, Hiroaki
Oiji, Nobuyasu
Nakano, Kenta
Okamura, Tadashi
Niimi, Kimie
Takahashi, Eiki
Guo, Long
Ikegawa, Shiro
Furuichi, Tatsuya
author_facet Kodama, Kazuki
Takahashi, Hiroaki
Oiji, Nobuyasu
Nakano, Kenta
Okamura, Tadashi
Niimi, Kimie
Takahashi, Eiki
Guo, Long
Ikegawa, Shiro
Furuichi, Tatsuya
author_sort Kodama, Kazuki
collection PubMed
description Desbuquois dysplasia (DD) type 1 is a rare skeletal dysplasia characterized by a short stature, round face, progressive scoliosis, and joint laxity. The causative gene has been identified as calcium‐activated nucleotidase 1 (CANT1), which encodes a nucleotidase that preferentially hydrolyzes UDP to UMP and phosphate. In this study, we generated Cant1 KO mice using CRISPR/Cas9‐mediated genome editing. All F0 mice possessing frameshift deletions at both Cant1 alleles exhibited a dwarf phenotype. Germline transmission of the edited allele was confirmed in an F0 heterozygous mouse, and KO mice were generated by crossing of the heterozygous breeding pairs. Cant1 KO mice exhibited skeletal defects, including short stature, thoracic kyphosis, and delta phalanx, all of which are observed in DD type 1 patients. The glycosaminoglycan (GAG) content and extracellular matrix space were reduced in the growth plate cartilage of mutants, and proliferating chondrocytes lost their typical flat shape and became round. Chondrocyte differentiation, especially terminal differentiation to hypertrophic chondrocytes, was impaired in Cant1 KO mice. These findings indicate that CANT1 is involved in the synthesis of GAG and regulation of chondrocyte differentiation in the cartilage and contribute to a better understanding of the pathogenesis of DD type 1.
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spelling pubmed-72629212020-06-03 CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage Kodama, Kazuki Takahashi, Hiroaki Oiji, Nobuyasu Nakano, Kenta Okamura, Tadashi Niimi, Kimie Takahashi, Eiki Guo, Long Ikegawa, Shiro Furuichi, Tatsuya FEBS Open Bio Research Articles Desbuquois dysplasia (DD) type 1 is a rare skeletal dysplasia characterized by a short stature, round face, progressive scoliosis, and joint laxity. The causative gene has been identified as calcium‐activated nucleotidase 1 (CANT1), which encodes a nucleotidase that preferentially hydrolyzes UDP to UMP and phosphate. In this study, we generated Cant1 KO mice using CRISPR/Cas9‐mediated genome editing. All F0 mice possessing frameshift deletions at both Cant1 alleles exhibited a dwarf phenotype. Germline transmission of the edited allele was confirmed in an F0 heterozygous mouse, and KO mice were generated by crossing of the heterozygous breeding pairs. Cant1 KO mice exhibited skeletal defects, including short stature, thoracic kyphosis, and delta phalanx, all of which are observed in DD type 1 patients. The glycosaminoglycan (GAG) content and extracellular matrix space were reduced in the growth plate cartilage of mutants, and proliferating chondrocytes lost their typical flat shape and became round. Chondrocyte differentiation, especially terminal differentiation to hypertrophic chondrocytes, was impaired in Cant1 KO mice. These findings indicate that CANT1 is involved in the synthesis of GAG and regulation of chondrocyte differentiation in the cartilage and contribute to a better understanding of the pathogenesis of DD type 1. John Wiley and Sons Inc. 2020-04-23 /pmc/articles/PMC7262921/ /pubmed/32277574 http://dx.doi.org/10.1002/2211-5463.12859 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Kodama, Kazuki
Takahashi, Hiroaki
Oiji, Nobuyasu
Nakano, Kenta
Okamura, Tadashi
Niimi, Kimie
Takahashi, Eiki
Guo, Long
Ikegawa, Shiro
Furuichi, Tatsuya
CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title_full CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title_fullStr CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title_full_unstemmed CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title_short CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
title_sort cant1 deficiency in a mouse model of desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262921/
https://www.ncbi.nlm.nih.gov/pubmed/32277574
http://dx.doi.org/10.1002/2211-5463.12859
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