A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-15 (CILD15) is caused by homozygous or compound heterozygous mutation in the CCDC40 gene (613799) on chromosome 17q25.

Primary ciliary dyskinesia-15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (summary by Becker-Heck et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Becker-Heck et al. (2011) reported 14 families with CILD15. Affected individuals had recurrent upper and lower airway infections; in addition, 5 (32%) had situs solitus (32%) and 11 (68%) showed situs inversus, consistent with randomization of left-right body asymmetry. Videomicroscopy analyses of respiratory cilia showed a severely altered beating pattern in all analyzed samples, with markedly reduced beating amplitudes, and rigid cilia with fast, flickery movements. There was no significant difference in cilia length between patients and controls, implying that ciliary movement can be disrupted in the absence of gross structural defects. Transmission electron microscopy studies showed defects in several axonemal structures, including occasional absent or eccentric central pairs, displacement of outer doublets, reductions in the mean number of inner dynein arms, and abnormal radial spokes and nexin links. Outer dynein arms appeared normal. There was also absence of the inner dynein arm component DNALI1 (610062) from respiratory ciliary axonemes, which accumulated in the apical cytoplasm, as well as an accumulation of GAS8 (605278) in the apical cytoplasm. The findings indicated that CCDC40 is necessary for correct assembly of at least 2 distinct axonemal complexes regulating ciliary beat: the inner dynein arms and the dynein regulatory complex. The phenotype was indistinguishable from that caused by CCDC39 (613798) mutations (CILD14; 613807) (Merveille et al., 2011), and further studies showed that CCDC40 deficiency affected axonemal localization of CCDC39, which was absent from the cilium and enriched in the apical cytoplasm at the ciliary base.

Antony et al. (2013) reported 37 families with primary ciliary dyskinesia due to biallelic mutations in the CCDC39 or CCDC40 genes. The phenotypes were indistinguishable. All patients had a classic PCD phenotype with a 'radial spoke defect,' including recurrent respiratory tract infections, pneumonia, rhinosinusitis, otitis media, and age-dependent bronchiectasis. Most patients presented in the early neonatal period with respiratory distress. About half had situs inversus, and infertility was documented in several males and females. Transmission electron microscopy of patient respiratory bronchial epithelial cells showed disorganization of the peripheral microtubular doublets, absent or shifted central pairs, and partial or complete loss of inner dynein arms. In 1 subset of samples, there was disarrangement of the outer microtubular doublets in 43% (CCDC39) and 36% (CCDC40) of cilia cross-sections, mainly involving translocation of peripheral microtubular doublets, as well as acentric or absent microtubular central pairs. Inner dynein arms were absent from 69% (CCDC39) and 90% (CCDC40) of cilia cross-sections. Outer dynein arms were apparent throughout. High speed video analysis of ciliated nasal brush biopsies showed that the majority of cilia were static or showed a stiff, rigid, and ineffective beat pattern. Immunohistochemical studies showed the presence of components of the radial spoke head and stalk, suggesting that the radial spoke structures are preserved in these patients. Antony et al. (2013) suggested that the term 'radial spoke defect' should be replaced with the more accurate term 'inner dynein arm (IDA) and microtubular disorganization defect.'

In 17 patients with primary ciliary dyskinesia-15, Becker-Heck et al. (2011) identified loss-of-function mutations in the CCDC40 gene (see, e.g., 613799.0001-613799.0004). All patients except 1 were homozygous or compound heterozygous for the mutations; a second mutant allele could not be found in 1 patient.

Antony et al. (2013) applied Sanger sequencing of the CCDC39 and CCDC40 genes and whole-exome sequencing to identify 12 different mutations in the CCDC39 gene and 13 different mutations in the CCDC40 gene among affected members of 37 (69%) of 54 unrelated families with primary ciliary dyskinesia and a 'radial spoke defect.' These mutations were absent from large control databases, segregated with the disorder in the families, and were predicted to result in premature protein truncation, likely associated with nonsense-mediated mRNA and complete loss of protein function. There was no clustering of the mutations to a particular region of either gene, suggesting that protein termination at any point leads to the same deleterious dysfunction. However, the 248delC mutation in CCDC40 (613799.0001) was the most common mutation, found in 63% of mutant alleles of Northern European origin worldwide.

Using a genetic screen, Becker-Heck et al. (2011) identified homozygous links (lnks) mutant mouse embryos that showed defects in left-right patterning, including situs inversus and left isomerism. The majority of lnks/lnks pups died before weaning. Hydrocephalus was present in 2 lnks/lnks pups that were examined. Becker-Heck et al. (2011) identified the lnks mutation as a ser792-to-ter (S792X) substitution in the middle of the coiled-coil domain of the Ccdc40 gene. Morpholino-mediated knockout of Ccdc40 in zebrafish resulted in laterality defects: either reversed organ patterning or randomized organ patterning. Becker-Heck et al. (2011) identified a gln778-to-ter (Q778X) mutation in the Ccdc40 gene in zebrafish with the locke (lok) phenotype, which is identical to the phenotype resulting from morpholino-mediated Ccdc40 knockdown. Scanning electron microscopy showed reduced length of cilia in nodal pit cells of lnks/lnks mice and reduced length of cilia in Kupffer vesicles and pronephric tubules of Ccdc40-morphant zebrafish.