Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia
Abstract Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an aut...
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Nature Portfolio
2023-11-01
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Series: | Nature Communications |
Online Access: | https://doi.org/10.1038/s41467-023-41651-6 |
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author | Ophélie Gourgas Gabrielle Lemire Alison L. Eaton Sultanah Alshahrani Angela L. Duker Jingjing Li Ricki S. Carroll Stuart Mackenzie Sarah M. Nikkel Care4Rare Canada Consortium Michael B. Bober Kym M. Boycott Monzur Murshed |
author_facet | Ophélie Gourgas Gabrielle Lemire Alison L. Eaton Sultanah Alshahrani Angela L. Duker Jingjing Li Ricki S. Carroll Stuart Mackenzie Sarah M. Nikkel Care4Rare Canada Consortium Michael B. Bober Kym M. Boycott Monzur Murshed |
author_sort | Ophélie Gourgas |
collection | DOAJ |
description | Abstract Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the cysteine 19 residue to phenylalanine or tyrosine. These individuals present with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulate most of the skeletal anomalies observed in the affected individuals. Our results suggest that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Overall, our findings support that heterozygous variants in MGP altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly. |
first_indexed | 2024-03-11T12:40:03Z |
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id | doaj.art-da25b033c7fc4486b1e0a997e6fbb6d0 |
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issn | 2041-1723 |
language | English |
last_indexed | 2024-03-11T12:40:03Z |
publishDate | 2023-11-01 |
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series | Nature Communications |
spelling | doaj.art-da25b033c7fc4486b1e0a997e6fbb6d02023-11-05T12:23:54ZengNature PortfolioNature Communications2041-17232023-11-0114112010.1038/s41467-023-41651-6Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasiaOphélie Gourgas0Gabrielle Lemire1Alison L. Eaton2Sultanah Alshahrani3Angela L. Duker4Jingjing Li5Ricki S. Carroll6Stuart Mackenzie7Sarah M. Nikkel8Care4Rare Canada ConsortiumMichael B. Bober9Kym M. Boycott10Monzur Murshed11Department of Medicine, McGill UniversityChildren’s Hospital of Eastern Ontario Research Institute, University of OttawaChildren’s Hospital of Eastern Ontario Research Institute, University of OttawaFaculty of Dental Medicine and Oral Health Sciences, McGill UniversityNemours Children’s HealthDepartment of Medicine, McGill UniversityNemours Children’s HealthNemours Children’s HealthUniversity of British ColumbiaNemours Children’s HealthChildren’s Hospital of Eastern Ontario Research Institute, University of OttawaDepartment of Medicine, McGill UniversityAbstract Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the cysteine 19 residue to phenylalanine or tyrosine. These individuals present with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulate most of the skeletal anomalies observed in the affected individuals. Our results suggest that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Overall, our findings support that heterozygous variants in MGP altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.https://doi.org/10.1038/s41467-023-41651-6 |
spellingShingle | Ophélie Gourgas Gabrielle Lemire Alison L. Eaton Sultanah Alshahrani Angela L. Duker Jingjing Li Ricki S. Carroll Stuart Mackenzie Sarah M. Nikkel Care4Rare Canada Consortium Michael B. Bober Kym M. Boycott Monzur Murshed Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia Nature Communications |
title | Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
title_full | Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
title_fullStr | Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
title_full_unstemmed | Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
title_short | Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
title_sort | specific heterozygous variants in mgp lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia |
url | https://doi.org/10.1038/s41467-023-41651-6 |
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