2. Academic Validation
  3. Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia

Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia

  • J Med Genet. 2014 Jul;51(7):470-4. doi: 10.1136/jmedgenet-2013-102218.
Amanda C Smith 1,  Alan J Mears 1,  Ryan Bunker 1,  Afsana Ahmed 1,  Malcolm MacKenzie 1,  Jeremy A Schwartzentruber 2,  Chandree L Beaulieu 1,  Emanuela Ferretti 3,  FORGE Canada Consortium,  Jacek Majewski 4,  Dennis E Bulman 1,  Fatma Cakmak Celik 5,  Kym M Boycott 6,  Gail E Graham 7
Affiliations

Affiliations

  • 1 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
  • 2 McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
  • 3 Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • 4 Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
  • 5 Division of Neonatology, Samsun Maternity and Children's Hospital, Samsun, Turkey.
  • 6 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • 7 Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
PMID: 24706940 DOI: 10.1136/jmedgenet-2013-102218
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.

Keywords

GPX4; Sedaghatian type; Spondylometaphyseal dysplasia; exome sequencing; lipid peroxidation.

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