Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia

• Published in: Nature genetics Vol. 44; no. 4; pp. 381 - 389
• Main Authors: Mitchison, Hannah M, Schmidts, Miriam, Loges, Niki T, Freshour, Judy, Dritsoula, Athina, Hirst, Rob A, O'Callaghan, Christopher, Blau, Hannah, Al Dabbagh, Maha, Olbrich, Heike, Beales, Philip L, Yagi, Toshiki, Mussaffi, Huda, Chung, Eddie M K, Omran, Heymut, Mitchell, David R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2012; Nature Publishing Group
• Subjects: 631/136/334/1874/763; 631/208/182; 631/208/2489/144; Agriculture; Amino Acid Sequence; Animal Genetics and Genomics; Animals; Axonemal Dyneins - biosynthesis; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chlamydomonas reinhardtii; Chlamydomonas reinhardtii - genetics; Cilia - genetics; Complex syndromes; Cytoplasm; Cytoplasm - genetics; Danio rerio; Dynein; Ear diseases; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genes; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human Genetics; Humans; Kartagener Syndrome - genetics; Male; Medical genetics; Medical sciences; Microtubule-Associated Proteins - chemistry; Microtubule-Associated Proteins - genetics; Molecular Sequence Data; Molecular weight; Motility; Movement disorders; Mutation; Pedigree; Phenotype; Physiological aspects; Polymorphism, Single Nucleotide; Proteins; Sequence Alignment; Sequence Analysis, DNA; Situs Inversus - genetics; Sperm; Zebrafish - genetics; Zebrafish Proteins - chemistry; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; United Kingdom; Enzyme; Malformation; Respiratory disease; Situs inversus; Immotile cilia syndrome; Hydrolases; ENT disease; Dynein ATPase; Molecular motor; Mutation; Congenital disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.1106

David Mitchell, Hannah Mitchison and colleagues identify a new
Chlamydomonas
protein required for the preassembly of axonemal dyneins before their transport into cilia. They further show that mutations in the homologous gene in humans result in primary ciliary dyskinesia accompanied by defects in the assembly of inner and outer dynein arms.
Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human
DNAAF3
gene in individuals from families with
situs inversus
and defects in the assembly of inner and outer dynein arms. Knockdown of
dnaaf3
in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations.
Chlamydomonas reinhardtii
PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes.