Primary ciliary dyskinesia-14 is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011).
For a general phenotypic description and a discussion ... Primary ciliary dyskinesia-14 is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).
Merveille et al. (2011) reported 19 unrelated families with CILD14 characterized primarily by chronic upper and lower airway infections. In addition, 9 (41%) patients had situs solitus, 10 (45%) had situs inversus, and 3 (14%) had heterotaxia. Two ... Merveille et al. (2011) reported 19 unrelated families with CILD14 characterized primarily by chronic upper and lower airway infections. In addition, 9 (41%) patients had situs solitus, 10 (45%) had situs inversus, and 3 (14%) had heterotaxia. Two of the cases with heterotaxia had documented polysplenia, consistent with Ivemark syndrome. Four affected males had oligoasthenospermia. Electron microscopy of respiratory cilia from 1 individual showed absence of inner dynein arms in all ciliary sections. There was also evidence of axonemal disorganization, including mislocalized peripheral doublets associated with either a displacement of the central pair, an absence of the central pair, or supernumerary central pairs. Transmission electron microscopy showed defective inner dynein arms, nexin links, and radial spokes, but normal outer dynein arms. There was abnormal localization of GAS8 (605178), which was confirmed to the cytoplasm and ciliary base in CCDC39-deficient cells. Optic microscopy showed dyskinetic or akinetic ciliary motility with a beating pattern characterized by reduced amplitude with rigid axonemes and fast, flickery movements. The phenotype was indistinguishable from primary ciliary dyskinesia-15 (CILD15; 613808) caused by CCDC40 (613799) mutations, which also shows ciliary depletion of GAS8 and CCDC39 (Becker-Heck et al., 2011). 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 microtubule 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 19 (38%) of 50 unrelated families with primary ciliary dyskinesia, Merveille et al. (2011) identified 14 different unambiguous loss of function mutations in the CCDC39 gene (see, e.g., 613798.0001-613798.0004). The mutations occurred in the homozygous or compound ... In 19 (38%) of 50 unrelated families with primary ciliary dyskinesia, Merveille et al. (2011) identified 14 different unambiguous loss of function mutations in the CCDC39 gene (see, e.g., 613798.0001-613798.0004). The mutations occurred in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. Respiratory cells from affected individuals showed loss of CCDC39 immunostaining. CCDC39 mutations were not found in 24 additional patients with primary ciliary dyskinesia without axonemal disorganization or in 216 sporadic heterotaxia cases. 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.