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


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.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Amanda C
AC
Smith
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Alan J
AJ
Mears
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Ryan
R
Bunker
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Afsana
A
Ahmed
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Malcolm
M
MacKenzie
McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
Jeremy A
JA
Schwartzentruber
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Chandree L
CL
Beaulieu
Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Emanuela
E
Ferretti
Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
Jacek
J
Majewski
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Dennis E
DE
Bulman
Division of Neonatology, Samsun Maternity and Children's Hospital, Samsun, Turkey.
Fatma Cakmak
FC
Celik
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.
Kym M
KM
Boycott
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Gail E
GE
Graham
D000595:Amino Acid Sequence; D001483:Base Sequence; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005979:Glutathione Peroxidase / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D020641:Polymorphism, Single Nucleotide; D011859:Radiography
D018389:Codon, Nonsense; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
GPX4; Sedaghatian type; Spondylometaphyseal dysplasia; exome sequencing; lipid peroxidation