Alternative titles; symbols
HGNC Approved Gene Symbol: CFAP300
Cytogenetic location: 11q22.1 Genomic coordinates (GRCh38): 11:102,047,437-102,084,554 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.1 | Ciliary dyskinesia, primary, 38 | 618063 | Autosomal recessive | 3 |
CFAP300 is an evolutionarily conserved protein essential for assembly of dynein arms (Fassad et al., 2018).
Using quantitative PCR, Fassad et al. (2018) found that expression of CFAP300 increased over time in cultured human ciliated epithelial cells, with a sharp rise around the time cells started to ciliate, before falling to a plateau phase. Phylogenetic analysis showed that CFAP300 orthologs are present in most species with motile cilia. CFAP300 orthologs are absent in nematode and lower plants that lack outer dynein arms, as well as from organisms that have outer arms but do not use IFT for intraflagellar transport. In Paramecium and Chlamydomonas, tagged Cfap300 localized mainly in cytoplasm, with a small amount in the ciliary component.
By RNA sequencing analysis, Hoben et al. (2018) found that CFAP300 was expressed in human ciliated respiratory cells and that expression of CFAP300 was upregulated during ciliogenesis.
Fassad et al. (2018) found that knockdown of Cfap300 in Paramecium led to loss of both inner and outer dynein arms and a defective swimming pattern with severely reduced velocity and significantly decreased cilia beat frequency, indicating that Cfap300 plays a role in dynein arm assembly. Knockdown of Ift139 in Paramecium resulted in aberrant accumulation of Cfap300 protein at tips of cilia during ciliogenesis, suggesting that Cfap300 is actively transported in cilia and recycled back to the cell via IFT-based transport. Likewise, analysis in Chlamydomonas showed that transport of Cfap300 to the flagellar matrix was also IFT dependent.
By in situ hybridization analysis of mouse embryos, Hoben et al. (2018) demonstrated that Cfap300 was involved in the function of motile nodal monocilia. Examination of human respiratory cilia by high-resolution immunofluorescence and transmission electron microscopy showed that CFAP300 loss of function resulted in defects of axonemal outer and inner dynein arms and ciliary immotility. Furthermore, immunofluorescence analysis of sperm flagella showed that CFAP300 deficiency led to male infertility associated with absence of outer and inner dynein arms in sperm flagella. Yeast 2-hybrid screening and pull-down assays revealed that CFAP300 interacted directly with the cytoplasmic outer and inner dynein arm assembly factor DNAAF2 (612517).
Hoben et al. (2018) reported that the CFAP300 gene contains 7 exons.
Hoben et al. (2018) reported that the CFAP300 gene maps to chromosome 11q22.1.
In 3 patients from 2 unrelated families with primary ciliary dyskinesia-38 (CILD38; 618063), Fassad et al. (2018) identified homozygous or compound heterozygous mutations in the CFAP300 gene (618058.0001-618058.0003). The mutations, which were found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Two sibs had a homozygous missense mutation and the third unrelated child was compound heterozygous for 2 nonsense mutations, suggesting a loss-of-function effect. Functional studies of the variants were not performed, but patient respiratory epithelial cell cilia were immotile with a combined loss of inner and outer dynein arms, and immunostaining showed decreased levels of the outer dynein arm marker DNAH5 (603335) and the inner dynein arm marker DNALI1 (602135). The cilia had a normal 9+2 ultrastructure. The patients were part of a cohort of 161 unrelated individuals with primary ciliary dyskinesia who were screened.
In 5 unrelated patients with CILD38, Hoben et al. (2018) identified homozygous loss-of-function mutations in the CFAP300 gene (618058.0002, 618058.0004, and 618058.0005). Patient respiratory epithelial cells and sperm flagella showed immotile cilia with loss of the axonemal inner and outer dynein arms, and immunofluorescence studies showed absence of DNAH5 and DNAH9 (603330) in the outer dynein arms and absence of DNALI1 and DNAH6 (603336) in the inner dynein arms. The mutations were found by targeted exome sequencing of 15 probands with primary ciliary dyskinesia.
In 2 brothers, born of consanguineous Pakistani parents (family 1), with primary ciliary dyskinesia-38 (CILD38; 618063), Fassad et al. (2018) identified a homozygous c.776A-G transition (c.776A-G, NM_032930.2) in exon 7 of the CFAP300 gene, resulting in a his259-to-arg (H259R) substitution at a highly conserved residue in the DUF4498 domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found only once in heterozygous state in the ExAC database (frequency of 8.242 x 10(-6)), but was not found in the Exome Variant Server, 1000 Genomes Project, or dbSNP databases. Functional studies of the variant were not performed, but patient respiratory epithelial cilia were immotile with a combined loss of inner and outer dynein arms.
In a boy, born of unrelated Indian parents (family 2), with primary ciliary dyskinesia-38 (CILD38; 618063), Fassad et al. (2018) identified compound heterozygous nonsense mutations in the CFAP300 gene: a c.361C-T transition (c.361C-T, NM_032930.2) in exon 4, resulting in an arg121-to-ter (R121X) substitution, and a c.154C-T transition in exon 2, resulting in a gln52-to-ter (Q52X; 618058.0003) substitution. Both mutations occurred in the DUF4498 domain. The mutations, which were found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were found in heterozygous state at low frequencies in the ExAC database in South Asian individuals (Q52X frequency of 1.653 x 10(-5) and R121X frequency of 8.254 x 10(-6)). Functional studies of the variants were not performed, but patient respiratory epithelial cilia were immotile with a combined loss of inner and outer dynein arms.
Hoben et al. (2018) identified a homozygous R121X mutation in 3 patients from 2 additional families with the disorder. One (proband OP-2334) was from a nonconsanguineous family of Italian descent with a family history of the disorder, and the other (proband OP-2249) was born of consanguineous Turkish parents. The mutation, which was found by targeted exome sequencing, segregated with the disorder in both families. The mutation was filtered against the dbSNP, 1000 Genomes Project, and gnomAD databases. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.
For discussion of the c.154C-T transition (c.154C-T, NM_032930.2) in exon 2 of the CFAP300 gene, resulting in a gln52-to-ter (Q52X) substitution, that was found in compound heterozygous state in a patient with primary ciliary dyskinesia-38 (CILD38; 618063) by Fassad et al. (2018), see 618058.0002.
In a girl (OP-2190), born of unrelated German parents, with primary ciliary dyskinesia-38 (CILD38; 618063), Hoben et al. (2018) identified a homozygous c.433A-T transversion (c.433A-T, NM_032930.2) in exon 4 of the CFAP300 gene, resulting in an arg145-to-ter (R145X) substitution. The mutation was found by targeted exome sequencing and filtered against the dbSNP, 1000 Genomes Project, and gnomAD databases. Segregation studies in the family were not possible. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.
In 2 unrelated patients (OI-87 of Israeli descent and OP-1416 of German descent) with primary ciliary dyskinesia-38 (CILD38; 618063), Hoben et al. (2018) identified a homozygous del/ins mutation (c.198_200delTTTinsCC, NM_032930.2) in the CFAP300 gene, resulting in a frameshift and premature termination (Phe67ProfsTer10). The mutation, which was found by targeted exome sequencing, was filtered against the dbSNP, 1000 Genomes Project, and gnomAD databases. Segregation studies in 1 family were consistent with autosomal recessive inheritance. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.
Fassad, M. R., Shoemark, A., le Borgne, P., Koll, F., Patel, M., Dixon, M., Hayward, J., Richardson, C., Frost, E., Jenkins, L., Cullup, T., Chung, E. M. K., Lemullois, M., Aubusson-Fleury, A., Hogg, C., Mitchell, D. R., Tassin, A.-M., Mitchison, H. M. C11orf70 mutations disrupting the intraflagellar transport-dependent assembly of multiple axonemal dyneins cause primary ciliary dyskinesia. Am. J. Hum. Genet. 102: 956-972, 2018. [PubMed: 29727692] [Full Text: https://doi.org/10.1016/j.ajhg.2018.03.024]
Hoben, I. M., Hjeij, R., Olbrich, H., Dougherty, G. W., Nothe-Menchen, T., Aprea, I., Frank, D., Pennekamp, P., Dworniczak, B., Wallmeier, J., Raidt, J., Nielsen, K. G., and 11 others. Mutations in C11orf70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to defects of outer and inner dynein arms. Am. J. Hum. Genet. 102: 973-984, 2018. [PubMed: 29727693] [Full Text: https://doi.org/10.1016/j.ajhg.2018.03.025]