PUBLICATION
Mutations in the Motile Cilia Gene DNAAF1 are Associated with Neural Tube Defects in Humans
- Authors
- Miao, C., Jiang, Q., Li, H., Zhang, Q., Bai, B., Bao, Y., Zhang, T.
- ID
- ZDB-PUB-160821-2
- Date
- 2016
- Source
- G3 (Bethesda) 6(10): 3307-3316 (Journal)
- Registered Authors
- Zhang, Ting
- Keywords
- DNAAF1, loss-of function, motile cilia, neural tube defects
- MeSH Terms
-
- Adolescent
- Adult
- Alleles
- Amino Acid Sequence
- Amino Acid Substitution
- Case-Control Studies
- Cell Line
- Cilia/genetics*
- DNA Mutational Analysis
- Female
- Gene Expression
- Genetic Association Studies*
- Genetic Variation
- Genotype
- Humans
- Male
- Mutation*
- Neural Tube Defects/diagnosis
- Neural Tube Defects/genetics*
- Neurogenesis/genetics
- Phenotype
- Young Adult
- PubMed
- 27543293 Full text @ G3 (Bethesda)
Citation
Miao, C., Jiang, Q., Li, H., Zhang, Q., Bai, B., Bao, Y., Zhang, T. (2016) Mutations in the Motile Cilia Gene DNAAF1 are Associated with Neural Tube Defects in Humans. G3 (Bethesda). 6(10):3307-3316.
Abstract
Neural tube defects (NTDs) are severe malformations of the central nervous system caused by complex genetic and environmental factors. Among genes involved in NTD, cilia related genes have been well defined and found to be essential for the completion of neural tube closure (NTC). We have carried out next-generation sequencing (NGS) on target genes in 373 NTDs and 222 healthy controls, and discovered eight disease-specific rare mutations in cilia related gene DNAAF1 DNAAF1 plays a central role in cytoplasmic preassembly of distinct dynein-arm complexes, and is expressed in some key tissues involved in neural system development such as neural tube, floor plate, embryonic node and brain ependyma epithelial cells in zebrafish and mouse. Therefore we evaluated the expression and functions of mutations in DNAAF1 in transfected cells to analyze the potential correlation of these mutants to NTDs in humans. One rare frameshift mutation (p.Gln341Argfs*10) resulted in significantly diminished DNAAF1 protein expression, compared to the wild-type. Another mutation, p.Lys231Gln, disrupted cytoplasmic preassembly of the dynein-arm complexes in cellular assay. Furthermore, results from NanoString assay on mRNA from NTD samples indicated that DNAAF1 mutants altered the expression level of NTC related genes. Altogether, these findings suggest that the rare mutations in DNAAF1 may contribute to the susceptibility for NTDs in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping