BackgroundCCDC39 and CCDC40 genes have recently been implicatedin primary ciliary dyskinesia (PCD) with innerdynein arms (IDA) defects and axonemal disorganization;their contribution to the disease is, however, unknown.With the aim to delineate CCDC39/CCDC40 mutationspectrum and associated phenotypes, we screened a largecohort of patients with IDA defects, and accuratelydescribed their clinical and ciliary phenotypes.MethodsAll CCDC39 and CCDC40 exons and intronic boundarieswere sequenced in 43 patients from 40 unrelated families.We recorded and compared clinical features (sex, origin,consanguinity, laterality defects, ages at first symptomsand evaluation, neonatal respiratory distress, airway infections,nasal polyposis, otitis media, bronchiectasis, infertility),ciliary beat frequency and quantitative ultrastructuralanalyses of cilia and sperm flagella.ResultsBiallelic CCDC39 or CCDC40 mutations were identified in30/34 (88.2%) unrelated families with IDA defects andaxonemal disorganization (22 and 8 families, respectively).Fourteen of the 28 identified mutations are novel. Nomutation was found in the 6 families with isolated IDAdefects. Patients with identified mutations shared a similarphenotype, in terms of both clinical features and ciliarystructure and function. The sperm flagellar ultrastructure,analyzed in 4/7 infertile males, evidenced abnormalitiessimilar to the ciliary ones.ConclusionsCCDC39 and CCDC40 mutations represent the majorcause of PCD with IDA defects and axonemal disorganization.Patients carrying CCDC39 or CCDC40 mutations arephenotypically indistinguishable. CCDC39 and CCDC40analyses in selected patients ensure to find mutations withhigh probability, even if clinical or ciliary phenotypes cannotprioritize one analysis over the other.
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