Abstract
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous syndrome that results from defects in motile cilia. The ciliary axoneme has a 9 + 2 microtubule structure consisting of nine peripheral doublets surrounding a central pair apparatus (CPA), which plays a critical role in regulating proper ciliary function. We have previously shown that mouse models with mutations in CPA genes CFAP221, CFAP54, and SPEF2 have a PCD phenotype with defects in ciliary motility. In this study, we investigated potential genetic interaction between these CPA genes by generating each combination of double heterozygous and double homozygous mutants. No detectable cilia-related phenotypes were observed in double heterozygotes, but all three double homozygous mutant lines exhibit early mortality and typically develop severe PCD-associated phenotypes of hydrocephalus, mucociliary clearance defects in the upper airway, and abnormal spermatogenesis. Double homozygous cilia are generally intact and display a normal morphology and distribution. Spermiogenesis is aborted in double homozygotes, with an absence of mature flagella on elongating spermatids and epididymal sperm. These findings identify genetic interactions between CPA genes and genetic mechanisms regulating the CPA and motile cilia function.
Highlights
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous syndrome that results from defects in motile cilia
We have previously shown that mouse models with mutations in central pair apparatus (CPA) genes ciliary and flagellar associated protein 221 (CFAP221), ciliary and flagellar associated protein 54 (CFAP54), and sperm flagellar protein 2 (SPEF2) each have a PCD phenotype that includes hydrocephalus, male infertility, and airway a bnormalities[26,27,28,29,30]
We investigated potential genetic interaction between CPA genes CFAP221, SPEF2, and CFAP54 by crossing the nm1054, bgh, and Cfap54gt/gt mouse models with mutations in those genes
Summary
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous syndrome that results from defects in motile cilia. SPAG6 mutants exhibit the full spectrum of PCD phenotypes, CPA structural defects, and reduced ciliary beat frequency[17,18,19], while mice lacking SPAG16L have only spermatogenic defects and male infertility but no other cilia-associated phenotypes[20]. Despite the paucity of studies investigating genetic interactions, the phenotypes of double mutant mice uncover new information about the roles of these genes in motile cilia function. We have previously shown that mouse models with mutations in CPA genes ciliary and flagellar associated protein 221 (CFAP221), ciliary and flagellar associated protein 54 (CFAP54), and sperm flagellar protein 2 (SPEF2) each have a PCD phenotype that includes hydrocephalus, male infertility, and airway a bnormalities[26,27,28,29,30]. CFAP221 and SPEF2 mutations were identified in human PCD patients[35,36,37], highlighting the importance of these CPA genes
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