HGNC Approved Gene Symbol: CCDC39
Cytogenetic location: 3q26.33 Genomic coordinates (GRCh38) : 3:180,614,008-180,679,489 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.33 | Ciliary dyskinesia, primary, 14 | 613807 | Autosomal recessive | 3 |
CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex (Merveille et al., 2011).
By searching databases for sequences similar to canine Ccdc39, Merveille et al. (2011) identified human CCDC39. The deduced 941-amino acid protein contains a domain similar to the N-terminal domain of structural maintenance of chromosomes (SMC) proteins (see 300040) followed by a domain similar to bacterial SMC proteins. The first SMC domain includes 6 coiled-coil regions, and the second includes 4 coiled-coil regions. Quantitative RT-PCR of adult human tissues showed predominant CCDC39 expression in nasal brushings and lower expression in lung and testis. In situ hybridization of developing mouse revealed specific Cdcd39 expression in node cells carrying motile cilia, in upper and lower airways, and in ependymal and choroid plexus cells. Western blot analysis of normal human respiratory epithelium detected CCDC39 at an apparent molecular mass of about 110 kD.
Merveille et al. (2011) determined that the CCDC39 gene contains 20 coding exons.
Hartz (2011) mapped the CCDC39 gene to chromosome 3q26.33 based on an alignment of the CCDC39 sequence (GenBank AL122120) with the genomic sequence (GRCh37).
In 19 unrelated families with primary ciliary dyskinesia-14 (CILD14; 613807), 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. Affected individuals had 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. 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. 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) 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 termination, 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. All patients had a classic homogeneous PCD phenotype, with respiratory tract infections, pneumonia, rhinosinusitis, otitis media, and age-dependent bronchiectasis. 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. Outer dynein arms were intact. 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 2 sibs, born to consanguineous Chinese parents, with CILD14, Chen et al. (2021) identified a homozygous missense mutation in the CCDC30 gene (L328P; 613798.0005). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents. Immunofluorescence staining with an anti-CCDC39 antibody showed that the CCDC39 protein was almost undetectable in the spermatozoa, which was confirmed by Western blot analysis.
Merveille et al. (2011) described 5 Old English sheepdogs (Bobtails) with symptoms of primary ciliary dyskinesia (CILD14; 613807). They traced the defect back to a founder female and identified 10 additional litters with primary ciliary dyskinesia. In 5 affected dogs, Merveille et al. (2011) identified homozygosity for an arg96-to-ter (R96X) mutation in the Ccdc39 gene that was predicted to truncate 90% of the Ccdc39 protein. All of 10 additional cases were homozygous for the mutation, and all of 10 obligate carriers were heterozygous for the mutation, as were 8 of 102 randomly sampled healthy Bobtails. Nasal and tracheal biopsies and transmission electron microscopy of respiratory epithelial cell cultures from affected dogs confirmed ciliary defects, including absent or eccentric central dynein arms. Sperm from an affected male showed oligoasthenospermia, with narrowed midpiece and shortened flagellum in 33% and 20% of sperm, respectively. Knockdown of Ccdc39 in zebrafish embryos at the 2-cell stage caused a dose-dependent increase in heart looping defects and other laterality defects at 36 hours postfertilization, further supporting a role of CCDC39 in cilia function.
In 5 patients, including 2 sibs, from 4 families with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a homozygous 1-bp deletion (2190delA) in exon 16 of the CCDC39 gene, resulting in a frameshift and premature termination in the SMC domain. Three of the 5 patients had laterality defects consistent with Kartagener syndrome. Four of the patients were of North African descent, and haplotype analysis indicated a founder effect in 3 families, whereas 1 family had a distinct haplotype, indicating a recurrent event.
In 2 unrelated patients with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a homozygous 1-bp deletion (1072delA) in exon 9 of the CCDC39 gene, resulting in a frameshift and premature termination in a coiled-coil region of the SMC domain. Another patient of German descent was compound heterozygous for 1072delA and another pathogenic mutation in the CCDC39 gene. Haplotype analysis of the 1072delA mutation indicated a founder effect. One patient had Ivemark syndrome, and 2 had oligoasthenospermia.
In affected members from 4 unrelated families with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a G-to-C transversion in intron 3 of the CCDC39 gene. Two sibs, of Turkish origin, were homozygous for the mutation, whereas the other 4 patients, including 2 unrelated individuals of French origin and 2 Danish sibs, were compound heterozygous for this mutation and another pathogenic mutation (see, e.g., 613798.0004). Haplotype analysis indicated a founder effect for the splice site mutation.
In 2 unrelated patients with primary ciliary dyskinesia-14 (CILD14; 613807), Merveille et al. (2011) identified a del/ins mutation (2357delGTAinsT) in exon 17 of the CCDC39 gene, resulting in a frameshift and premature termination. Each patient was compound heterozygous for this mutation and another pathogenic mutation (see, e.g., 613798.0003). One patient was from France and the other from the West Indies/Senegal, and haplotype analysis indicated a founder effect for the del/ins mutation.
In a brother and sister, born to consanguineous Chinese parents, with primary ciliary dyskinesia-14 (CILD14; 613807), Chen et al. (2021) identified a homozygous c.983T-C transition (c.983T-C, NM_181426.1) in the CCDC30 gene, resulting in a leu328-to-pro (L328P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present at a low frequency (0.0003193) in East Asian populations in the gnomAD database. Immunofluorescence staining with an anti-CCDC39 antibody showed that the CCDC39 protein was almost undetectable in the spermatozoa, which was confirmed by Western blot analysis.
Antony, D., Becker-Heck, A., Zariwala, M. A., Schmidts, M., Onoufriadis, A., Forouhan, M., Wilson, R., Taylor-Cox, T., Dewar, A., Jackson, C., Goggin, P., Loges, N. T., and 23 others. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum. Mutat. 34: 462-472, 2013. [PubMed: 23255504] [Full Text: https://doi.org/10.1002/humu.22261]
Becker-Heck, A., Zohn, I. E., Okabe, N., Pollock, A., Lenhart, K. B., Sullivan-Brown, J., McSheene, J., Loges, N. T., Olbrich, H., Haeffner, K., Fliegauf, M., Horvath, J., and 9 others. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nature Genet. 43: 79-84, 2011. [PubMed: 21131974] [Full Text: https://doi.org/10.1038/ng.727]
Chen, D., Liang, Y., Li, J., Zhang, X., Zheng, R., Wang, X., Zhang, H., Shen, Y. A novel CCDC39 mutation causes multiple morphological abnormalities of the flagella in a primary ciliary dyskinesia patient. Reprod. Biomed. Online 43: 920-930, 2021. [PubMed: 34674941] [Full Text: https://doi.org/10.1016/j.rbmo.2021.07.005]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/9/2011.
Merveille, A.-C., Davis, E. E., Becker-Heck, A., Legendre, M., Amirav, I., Bataille, G., Belmont, J., Beydon, N., Billen, F., Clement, A., Clercx, C., Coste, A., and 32 others. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genet. 43: 72-78, 2011. [PubMed: 21131972] [Full Text: https://doi.org/10.1038/ng.726]