Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype.
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.
Fernandez-Gonzalez
Angeles
A
Division of Newborn Medicine, Enders 970, 300 Longwood Avenue, Children's Hospital Boston, Boston, MA 02115, USA.
Kourembanas
Stella
S
Wyatt
Todd A
TA
Mitsialis
S Alex
SA
D000263:Adenylate Kinase / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002923:Cilia / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007619:Kartagener Syndrome / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010641:Phenotype; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D014018:Tissue Distribution; D019076:Transgenes
D007527:Isoenzymes; D010047:Ovalbumin; D000263:Adenylate Kinase; C538858:adenylate kinase 7, mouse
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