title: Mutations in the Motile Cilia Gene DNAAF1 Are Associated with Neural Tube Defects in Humans.
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 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.
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, 100020, China.
authors.forename: Chunyue
authors.initials: C
authors.lastname: Miao
authors.affiliation: Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China teaco@126.com zhangtingcv@126.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China.
authors.forename: Baoling
authors.initials: B
authors.lastname: Bai
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, 100020, China Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, China teaco@126.com zhangtingcv@126.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002460:Cell Line; D002923:Cilia / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009436:Neural Tube Defects / Q000175:diagnosis / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics; D010641:Phenotype; D055815:Young Adult
keywords: DNAAF1; loss-of function; motile cilia; neural tube defects