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. Epub 2014 Jul 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Arthrogryposis / genetics*
  • Arthrogryposis / metabolism
  • Arthrogryposis / pathology
  • Consanguinity
  • Exome
  • Female
  • Gene Knockdown Techniques
  • Genetic Complementation Test
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Mutation, Missense*
  • Neuromuscular Junction / metabolism*
  • Neuromuscular Junction / pathology
  • Nuclear Proteins / genetics*
  • Pedigree
  • Saudi Arabia
  • Stillbirth
  • Zebrafish


  • Muscle Proteins
  • Nuclear Proteins
  • ZBTB42 protein, human

Supplementary concepts

  • Lethal congenital contracture syndrome 1