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

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.

• Authors: Nisha Patel, Laura L Smith, Eissa Faqeih, Jawahir Mohamed, Vandana A Gupta, Fowzan S Alkuraya
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 24 Pg. 6584-93 (Dec 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 25055871 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Muscle Proteins
• Nuclear Proteins
• ZBTB42 protein, human

Topics

• Amino Acid Sequence
• Animals
• Animals, Genetically Modified
• Arthrogryposis (genetics, metabolism, 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, metabolism, pathology)
• Mutation, Missense
• Neuromuscular Junction (metabolism, pathology)
• Nuclear Proteins (genetics)
• Pedigree
• Saudi Arabia
• Stillbirth
• Zebrafish