PUBLICATION
Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome
- Authors
- Burns, R., Majczenko, K., Xu, J., Peng, W., Yapici, Z., Dowling, J.J., Li, J.Z., Burmeister, M.
- ID
- ZDB-PUB-141102-2
- Date
- 2014
- Source
- Neurology 83(23): 2175-82 (Journal)
- Registered Authors
- Li, Jun
- Keywords
- none
- MeSH Terms
-
- Ataxia/diagnosis
- Ataxia/genetics*
- Cell Cycle Proteins/genetics*
- Genes, Recessive/genetics*
- Genetic Linkage/genetics
- Genetic Predisposition to Disease*
- Genotype
- Homozygote
- Humans
- Mutation/genetics*
- Polymorphism, Single Nucleotide/genetics*
- RNA Splice Sites/genetics
- Turkey
- PubMed
- 25361784 Full text @ Neurology
Citation
Burns, R., Majczenko, K., Xu, J., Peng, W., Yapici, Z., Dowling, J.J., Li, J.Z., Burmeister, M. (2014) Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome. Neurology. 83(23):2175-82.
Abstract
Objective To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.
Methods Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription-PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.
Results We identified a homozygous mutation at the invariant +1 position (c.964+1G>A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities.
Conclusions Our results suggest that CWF19L1 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping