Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia
Abstract
Background: Sedaghatian-type spondylometaphyseal dysplasia (SSMD) is a neonatal lethal form of spondylometaphyseal dysplasia characterised by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. As part of the FORGE Canada Consortium we studied two unrelated families to identify the genetic aetiology of this rare disease. Methods and results: Whole exome sequencing of a child affected with SSMD and her unaffected parents identified two rare variants in GPX4. The first (c.587+5G>A) was inherited from the mother, and the second (c.588–8_588-4del) was de novo (NM_001039848.1); both were predicted to impact splicing of GPX4. In vitro studies confirmed the mutations spliced out part of exon 4 and skipped exon 5, respectively, with both resulting in a frameshift and premature truncation of GPX4. Subsequently, a second child with SSMD was identified; although DNA from the child was not available, the two unaffected parents were found by Sanger sequencing to each carry the same heterozygous stop mutation in exon 3 of GPX4, c.381C>A, p.Tyr127* (NM_001039848.1). Conclusions: Our identification of truncating mutations in GPX4 in two families affected with SSMD supports the pathogenic role of mutated GPX4 in this very rare disease. GPX4 is a member of the glutathione peroxidase family of antioxidant defence enzymes and protects cells against membrane lipid peroxidation. GPX4 is essential for early embryo development, regulating anti-oxidative and anti-apoptotic activities. Our findings highlight the importance of this enzyme in development of the cardiac, nervous, and skeletal systems.
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Whole exome sequencing found GPX4 point mutations that cause premature truncation and loss of GPX4 enzyme activity in an affected child and family.
“Whole exome sequencing of an affected child and its family identified point mutations in GPX4 that caused premature truncation of the GPX4 protein, which results in the lack of GPX4 enzyme activity [53].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [53]
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Viswanathan, V. S. (2015) · doi:10.7916/d8h9940v · Cited by 4 · see citing works
Tise, C. G., Ashton, K. A., Hayr, L. D., Lee, K. T., Patkar, O. L., Krzesinski, E. I., Bassetti, J. A., Carter, E. M., Raggio, C., Zankl, A., et al. (2024) · Genetics in Medicine Open · doi:10.1016/j.gimo.2024.101958 · Cited by 2 · see citing works
Fradejas‐Villar, N., & Schweizer, U. (2018) · Molecular and integrative toxicology · doi:10.1007/978-3-319-95390-8_9 · Cited by 2 · see citing works
Selenoproteins in Cardiovascular Redox Pathology
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A housekeeping gene search to analyze expression changes of individual genes in Macaca mulatta
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Disorders of Peptide and Amine Metabolism
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- Authors
- Smith, A. C., Mears, A. J., Bunker, R., Ahmed, A., MacKenzie, M., Schwartzentruber, J. A., Beaulieu, C. L., Ferretti, E., FORGE Canada Consortium, Majewski, J., Bulman, D. E., Celik, F. C., Boycott, K. M., & Graham, G. E.
- Affiliations
- University of Ottawa (CA)
- McGill University and Génome Québec Innovation Centre (CA)
- Children's Hospital of Eastern Ontario (CA)
- McGill University (CA)
- Division of Neonatology, Samsun Maternity and Children's Hospital, Samsun, Turkey
- Corresponding author
- Boycott, Kym M
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2014-04-04
- Volume
- 51
- Issue
- 7
- Pages
- 470-474
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2167879855
- Cited by
- 87
- References
- 23
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 12 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 2 · 2016: 8 · 2015: 2
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- spondylometaphyseal dysplasia, GPX4, aberrant splicing, exon skipping, frameshift mutation, premature truncation, de novo mutations, cardiac conduction disorders, platyspondyly, metaphyseal chondrodysplasia, antioxidant defense, embryonic development
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Amino Acid Sequence, Base Sequence, Consanguinity, DNA Mutational Analysis, Female, Glutathione Peroxidase, Humans, Infant, Newborn, Male, Molecular Sequence Data, Osteochondrodysplasias, Pedigree, Radiography, Frameshift Mutation, Fatal Outcome, Codon, Nonsense, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Association Studies, HEK293 Cells
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