PUBLICATION
ZBTB42 Mutation Defines A Novel Lethal Congenital Contracture Syndrome (LCCS6)
- Authors
- Patel, N., Smith, L.L., Faqeih, E., Mohamed, J., Gupta, V.A., Alkuraya, F.S.
- ID
- ZDB-PUB-140728-23
- Date
- 2014
- Source
- Human molecular genetics 23(24): 6584-93 (Journal)
- Registered Authors
- Gupta, Vandana A
- Keywords
- none
- MeSH Terms
-
- Muscle, Skeletal/innervation
- Muscle, Skeletal/metabolism*
- Muscle, Skeletal/pathology
- Female
- Arthrogryposis/genetics*
- Arthrogryposis/metabolism
- Arthrogryposis/pathology
- High-Throughput Nucleotide Sequencing
- Nuclear Proteins/genetics*
- Gene Knockdown Techniques
- Pedigree
- Animals
- Amino Acid Sequence
- Zebrafish
- Neuromuscular Junction/metabolism*
- Neuromuscular Junction/pathology
- Humans
- Infant, Newborn
- Animals, Genetically Modified
- Stillbirth
- Exome
- Male
- Muscle Proteins/genetics*
- Molecular Sequence Data
- Consanguinity
- Mutation, Missense*
- Saudi Arabia
- Homozygote
- Genetic Complementation Test
- PubMed
- 25055871 Full text @ Hum. Mol. Genet.
Citation
Patel, N., Smith, L.L., Faqeih, E., Mohamed, J., Gupta, V.A., Alkuraya, F.S. (2014) ZBTB42 Mutation Defines A Novel Lethal Congenital Contracture Syndrome (LCCS6). Human molecular genetics. 23(24):6584-93.
Abstract
Lethal Congenital Contracture Syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenital (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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping