PXD043374

PXD043374 is an original dataset announced via ProteomeXchange.

Title	Heterozygous variants in MGP lead to endoplasmic reticulum stress causing spondyloepiphyseal dysplasia
Description	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 presented 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 recapitulated most of the skeletal anomalies observed in the affected individuals. We demonstrated that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Our findings support that heterozygous variants in MGP altering Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_09:49:46.898.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sultanah Alshahrani
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetic acid derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-28 11:50:30	ID requested
⏵ 1	2024-01-26 09:49:48	announced

10.1038/s41467-023-41651-6;

Gourgas O, Lemire G, Eaton AJ, Alshahrani S, Duker AL, Li J, Carroll RS, Mackenzie S, Nikkel SM, Bober MB, Boycott KM, Murshed M, Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia. Nat Commun, 14(1):7054(2023) [pubmed]

submitter keyword: skeletal dysplasia,MGP, spondyloepiphyseal dysplasia

Monzur Murshed
contact affiliation	Professor, Department of Medicine and Faculty of Dental Medicine and Oral Health Sciences Principal Investigator; Shriners Hospital for Children, Canada 1529 Cedar Avenue, Montreal, QC H3G 1A6, Canada
contact email	monzur.murshed@mcgill.ca
lab head
Sultanah Alshahrani
contact affiliation	McGill univeristy
contact email	sultanah.al-shahrani@mail.mcgill.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043374
     1. Label: PRIDE project
     2. Name: Heterozygous variants in MGP lead to endoplasmic reticulum stress causing spondyloepiphyseal dysplasia