Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia

Nature Communications · 12 authors, 10 centres

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TL;DR

This preclinical study used a mouse model to show that a heterozygous MGP C19F variant causes skeletal anomalies like shorter bones and low bone mass, likely due to ER stress and impaired chondrocyte function.

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Researchers created a mouse model (Mgp+/56G>T) carrying a human C19F variant. Analysis of 6-week-old mice revealed shorter vertebrae and long bones, craniofacial anomalies with midface retrusion, and osteopenia (reduced trabecular bone volume and number). Histology indicated poor bone remodeling with reduced osteoblast and osteoclast numbers, despite non-significant changes in mineral apposition rate. In vitro and mass spectrometry analyses suggested the variant impairs MGP signal peptide processing, leading to its accumulation in the endoplasmic reticulum. Immunofluorescence in mouse vertebrae showed increased ER stress markers (like calnexin) in chondrocytes.

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preclinical research

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ORIGINAL PAPER

PMC10624854

Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia

Nature Communications

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ABSTRACT

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. Subject terms: Diseases, Gene expression, Bone development, Cartilage development, CRISPR-Cas9 genome editing

CITATION EXPORT

Ophélie Gourgas, Gabrielle Lemire, Alison J Eaton et al.. Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-41651-6

AUTHORS

12 · 10 CENTRES

Ophélie Gourgas, Gabrielle Lemire, Alison J Eaton, Sultanah Alshahrani, Angela L Duker, Jingjing Li, Ricki S Carroll, Stuart Mackenzie, Sarah M Nikkel, Michael B Bober, Kym M Boycott, Monzur Murshed

1Department of Medicine, McGill University, Montreal, QC Canada
2Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON Canada
3Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON Canada
4Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA USA
5University of Alberta, Edmonton, AB Canada
6Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC Canada
7Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
8Nemours Children’s Health, Wilmington, DE USA
9University of British Columbia, Vancouver, BC Canada
10Shriners Hospitals for Children ˗ Canada, Montreal, QC Canada