DNAI2 Mutations Cause Primary Ciliary Dyskinesia with Defects in the Outer Dynein Arm

Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2008; 83(5):547-58. DOI: 10.1016/j.ajhg.2008.10.001
Source: PubMed


Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.

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    • "The axonemal dynein intermediate chain gene, DNAI1 (located on chromosome 9p12–21), and the axonemal dynein heavy chain gene, DNAH5 (located on chromosome 5p15–14), are two of the best studied genes in PCD/KS. Mutations in these genes may result in absence of ODA, leading to abnormalities of ciliary ultrastructure and motor function.3144454647 A number of studies have shown the relationship between genetic mutation and PCD/KS phenotypes, thus driving the investigation of the underlying pathologic mechanism. "
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    • "Similarly, homozygosity mapping in consanguineous families has been used to identify mutations in other structural proteins, including the radial spoke head proteins 9 (RSPH9; MIM 612648) and 4A (RSPH4A; MIM 612647), both associated with absence of the central pair and motility defects (58, 72). Other examples of mutated axonemal proteins associated with PCD discovered using the candidate gene approach include intermediate dynein chain DNAI2 (MIM 605483) (60), which comprise about 2% of PCD patients (55), and TXNDC3 (MIM 607421) (56). "
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    • "This term is annotated to three passerine PSGs: coiled-coil domain containing 40 (CCDC40), axonemal dynein intermediate chain 2 (DNAI2), and cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1). DNAI2 protein is a component of respiratory ciliary axonemes and sperm flagella, and human DNAI2 mutations are associated with respiratory tract dysfunction and infertility [57]. DYNC2LI1 is present in the mammalian ciliary axoneme [58]. "
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