2. Academic Validation
  3. ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6)

ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6)

  • Hum Mol Genet. 2014 Dec 15;23(24):6584-93. doi: 10.1093/hmg/ddu384.
Nisha Patel 1,  Laura L Smith 2,  Eissa Faqeih 3,  Jawahir Mohamed 1,  Vandana A Gupta 4,  Fowzan S Alkuraya 5
Affiliations

Affiliations

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 2 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia and.
  • 4 Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA, falkuraya@kfshrc.edu vgupta@enders.tch.harvard.edu.
  • 5 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia falkuraya@kfshrc.edu vgupta@enders.tch.harvard.edu.
PMID: 25055871 DOI: 10.1093/hmg/ddu384
Abstract

Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome Sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.

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