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Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia
  1. Amanda C Smith1,
  2. Alan J Mears1,
  3. Ryan Bunker1,
  4. Afsana Ahmed1,
  5. Malcolm MacKenzie1,
  6. Jeremy A Schwartzentruber2,
  7. Chandree L Beaulieu1,
  8. Emanuela Ferretti3,
  9. FORGE Canada Consortium,
  10. Jacek Majewski4,
  11. Dennis E Bulman1,
  12. Fatma Cakmak Celik5,
  13. Kym M Boycott1,6,
  14. Gail E Graham6
  1. 1Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  2. 2McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada
  3. 3Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  4. 4Department of Human Genetics, McGill University, Montréal, Quebec, Canada
  5. 5Division of Neonatology, Samsun Maternity and Children's Hospital, Samsun, Turkey
  6. 6Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  1. Correspondence to Dr Kym Boycott, Department of Genetics, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1; kboycott{at}cheo.on.ca

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.

  • Spondylometaphyseal dysplasia
  • Sedaghatian type
  • exome sequencing
  • GPX4
  • lipid peroxidation

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