Mutations in CCDC39 and CCDC40 are a major cause of primary ciliary dyskinesia with microtubule disorganisation

摘要

Primary ciliary dyskinesia (PCD) is a genetically heterogeneousinherited disorder characterised by recurrentrespiratory tract infections, bronchiectasis and subfertilitywhich arises from cilia/sperm dysmotility associated withaxonemal ultrastructural abnormalities. Laterality is randomizedwith ~50% of patients having situs inversus. Upto 15% of PCD cases show perturbation of the 9+2 microtubulestructure and loss of the inner dynein arms, andthese have tended to be referred to as ‘radial spoke defect’cases. The radial spokes are essential for axoneme motility,mediating signal transduction between the central microtubularpair and dynein arm motors. Two genes causingthis specific ultrastructural defect are known: CCDC39(Merveille et. al., Nat Genet. 2011 43:72-8) and CCDC40(Becker-Heck et. al. Nat Genet. 2011 43:79-84). Wesequenced these genes in 22 PCD families with an ultrastructuraldefect involving microtubule disorganisation,either with or without accompanying loss of the innerdynein arms. We found recesively inherited CCDC39mutations in 8/22 families and CCDC40 mutations in 7/22families in the cohort, jointly accounting for a remarkable68% (15/22) of families. The majority of CCDC39 andCCDC40 mutations were nonsense or frameshift resultingin early protein truncation, predicted to cause major disruptionto the axoneme. Furthermore, there was a preponderanceof homozygous mutations accounting for disease,even in families from outbred populations. Our resultshighlight the key role of the CCDC39 and CCDC40 genesin PCD with radial spoke defect, and suggest that diseaseis associated with complete protein loss (null alleles).These two genes represent prime targets for genetic testingin this disease phenotype. Work is in progress to identifythe disease genes in the remaining patients within thissubgroup, by next generation whole exome sequencing.