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Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype.

ABSTRACT: Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder, characterized by progressive development of bronchiectasis, inflammation, and features characteristic of chronic obstructive pulmonary disease. We report here that a murine mutation of the evolutionarily conserved adenylate kinase 7 (Ak7) gene results in animals presenting with pathological signs characteristic of PCD, including ultrastructural ciliary defects and decreased ciliary beat frequency in respiratory epithelium. The mutation is associated with hydrocephalus, abnormal spermatogenesis, mucus accumulation in paranasal passages, and a dramatic respiratory pathology upon allergen challenge. Ak7 appears to be a marker for cilia with (9 + 2) microtubular organization. This is suggested by its tissue specificity of expression and also the stringent conservation of Ak7 ortholog structure only in protozoans and metazoans possessing motile (9 + 2) cilia. Collectively, our results indicate an ancestral and crucial role of Ak7 in maintaining ciliary structure and function, and suggest that mutations of the human ortholog may underlie a subset of genetically uncharacterized PCD cases.

SUBMITTER: Fernandez-Gonzalez A

PROVIDER: S-EPMC2645528 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype.

Fernandez-Gonzalez Angeles A Kourembanas Stella S Wyatt Todd A TA Mitsialis S Alex SA

American journal of respiratory cell and molecular biology 20080905 3

Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder, characterized by progressive development of bronchiectasis, inflammation, and features characteristic of chronic obstructive pulmonary disease. We report here that a murine mutation of the evolutionarily conserved adenylate kinase 7 (Ak7) gene results in animals presenting with pathological signs characteristic of PCD, including ultrastructural ciliary defects and decreased ciliary beat frequency in resp ...[more]

PMID: 18776131

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating.MethodsGenetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion.ResultsA single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells.ConclusionMutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.

Project description:BACKGROUND: Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%. METHODS: The coding sequence of DNAI1 was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families. RESULTS: Three previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in DNAI1 (54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort. CONCLUSIONS: The worldwide involvement of DNAI1 mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.

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Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype.

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Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype.

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