Alternative titles; symbols
HGNC Approved Gene Symbol: CFAP221
SNOMEDCT: 233666007;
Cytogenetic location: 2q14.2 Genomic coordinates (GRCh38) : 2:119,544,449-119,660,323 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.2 | Ciliary dyskinesia, primary, 55 | 279000 | Autosomal recessive | 3 |
CFAP221 is expressed in spermatogenic and motile ciliated cell types and involved in the regulation of flagellar and ciliary motility (Lee et al., 2008; DiPetrillo and Smith, 2011).
Lee et al. (2008) cloned the cDNA of mouse Cfap221, also known as Pcdp1, encoding a 836-amino-acid protein. Sequence alignment showed that Pcdp1 was highly conserved among higher eukaryotes, and that orthologs were present in species ranging from ciliated unicellular eukaryotes to humans, but not in Chlamydomonas reinhardtii. Northern blot analysis detected a 2.5-kb Pcdp1 transcript only in mouse testis. In situ hybridization further showed that Pcdp1 was expressed in cells undergoing spermatogenesis, as well as in the ciliated respiratory epithelial cells lining the sinuses, trachea, and bronchi of mice. Immunohistochemical analysis revealed that PCDP1 protein was expressed in spermatocytes and spermatids and localized to the flagella of mature spermatozoa, the cilia of mouse and human respiratory epithelial cells, and the cilia of ependymal cells in human brain.
DiPetrillo and Smith (2010) identified Chlamydomonas reinhardtii Pcdp1, termed Fap221, and found that it shared high sequence identity with mouse Pcdp1, but contained 1 calmodulin (CaM; see 114180)-binding site as compared to 2 in mouse Pcdp1.
Using RT-PCR, Bustamante-Marin et al. (2020) examined the expression and localization of CFAP221 in normal human bronchial epithelial cells and observed that expression increased during ciliated cell differentiation. Western blotting and immunofluorescence showed that CFAP221 is not expressed in undifferentiated airway cells and is localized primarily to the axoneme in in differentiated ciliated cells.
By RT-PCR analysis across multiple organs in adult mice, Shen et al. (2025) observed a conspicuous predominance of Cfap221 expression within testicular tissue, with significant expression starting on postnatal day (P) 10, peaking at P42, and maintaining a consistent expression profile thereafter. Immunofluorescence analysis of mouse testis sections showed that Cfap221 is predominantly localized to round and elongating/elongated spermatids during spermiogenesis. Immunofluorescence staining of human and mouse sperm revealed cytoplasmic expression in spermatogonia, spermatocytes, and round spermatids, whereas in elongating and elongated spermatids, CFAP221 was detected in the head and flagellum. To map the average expression of Cfap221 across all cell clusters, the authors performed single-cell RNA sequencing of mouse testicular germ cells and observed expression primarily in spermatocytes, round spermatids, and elongating/elongated spermatids, and noted similar transcriptional profiles for other cilia- and flagella-associated proteins, including Cfap74 (620187), Cfap194, Cfap246, and Cfap297. The authors suggested that CFAP221 might play a significant role in the assembly of sperm flagella by interacting with flagellum-related proteins.
Lee et al. (2008) determined that mouse Pcdp1 gene comprises 23 exons.
Stumpf (2019) mapped the CFAP221 gene to chromosome 2q14.2 based on an alignment of the CFAP221 sequence (GenBank BC036530.1) with the genomic sequence (GRCh38).
DiPetrillo and Smith (2010) found that C. reinhardtii Fap221 protein bound to calcium-calmodulin (Ca(2+)-CaM) and formed a single complex of approximately 110 kD with Fap54, Fap46, and Fap74 in the C1d projection of the central apparatus. The Ca(2+)-CaM interacting complex was required for the motility of C. reinhardtii.
Using a functional and structural approach combined with C. reinhardtii mutants lacking the C1d projection and distinct subsets of dynein arms, DiPetrillo and Smith (2011) demonstrated that the Pcdp1 complex coordinated the activity of dynein isoforms to produce ciliary motility, likely through interactions with the radial spokes.
In 3 French Canadian sibs (family UNC-1200) with primary ciliary dyskinesia (CILD55; 279000), Bustamante-Marin et al. (2020) identified compound heterozygosity for mutations in the CFAP221 gene: a 5-bp deletion (618704.0001) and a splice site mutation (618704.0002). The mutations, which were found by whole-exome sequencing (WES), segregated with disease in the family and were not found in the gnomAD database. Immunofluorescence analysis of patient ciliated cells revealed absence of CFAP221.
Using next-generation sequencing in a cohort of 920 patients with a suspected diagnosis of primary ciliary dyskinesia (PCD), Wohlgemuth et al. (2024) identified a 39-year-old German woman, born of consanguineous parents, who was homozygous for a 1-bp duplication (618704.0003) in the CFAP221 gene. By WES in an 18-year-old Polish man with mild PCD, Rabiasz et al. (2025) identified homozygosity for the same 1-bp duplication reported by Wohlgemuth et al. (2024).
In a 42-year-old Japanese man with PCD and infertility due to obstructive azoospermia, Ito et al. (2025) identified compound heterozygosity for deletions in the CFAP221 gene: a 4-bp deletion (618704.0004) within exon 15 on one chromosome, and a larger deletion spanning exons 15 to 21 (618704.0005) on the other.
By WES in 2 unrelated Chinese men with infertility due to multiple morphologic abnormalities of the sperm flagella, who reported no symptoms of PCD but declined further evaluation, Shen et al. (2025) identified compound heterozygous mutations in the CFAP221 gene. Both men carried the same splice site mutation (c.2318+4del) but different missense mutations (R430W and G255R). Their unaffected parents were carriers of the mutations, which were not found in public variant databases except for R430W, which was present at low minor allele frequency in the gnomAD database.
Lee et al. (2008) showed that mice homozygous for the nm1054 mutation, a recessive, pleiotropic mutation caused by an approximately 400-kb deletion on chromosome 1 that contains 6 genes, developed phenotypes commonly associated with primary ciliary dyskinesia (PCD). The nm1054 mutant mice did not express Pcdp1, and transgenic introduction of wildtype Pcdp1 rescued the PCD phenotypes. These results demonstrated that PCD phenotypes in the mutant mice resulted from the loss of Pcdp1.
Finn et al. (2014) compared 2 mouse models of PCD, nm1054 and bgh, which have mutations in the Pcdp1 and Spef2 (610172) genes, respectively. Both mutants exhibited hydrocephalus with increased gliosis and damage to multiple cell types. Phenotype severity was strain dependent, as it was more intense in mice from a C57BL/6J background than from a 129S6/SvEvTac background. The phenotypes were likely due to intraventricular pressure exerted by cilia-driven cerebrospinal fluid (CSF) accumulating in lateral ventricles. However, in vivo and ex vivo flow data demonstrated that decreased cilia function and impaired CSF flow were independent of genetic background. These results indicated that genetic modifiers also likely influenced the severity of hydrocephalus in these models.
To confirm the impact of CFAP221 deficiency on ciliary function in a model organism, Rabiasz et al. (2025) used RNAi to silence the CFAP221 homolog in S. mediterranea worms. The mutant worms showed a significantly slower locomotion speed than control worms, and analysis of ciliary motility in the epithelial cells of the worm head region revealed asynchronous and slower ciliary beating in the cfap221-silenced worms compared to controls.
In 3 French Canadian sibs (family UNC-1200) with primary ciliary dyskinesia (CILD55; 279000), Bustamante-Marin et al. (2020) identified compound heterozygosity for mutations in the CFAP221 gene: a 5-bp deletion (c.2303_2307delTAGAA, NM_001271049.2) in exon 22, causing a frameshift predicted to result in a premature termination codon (Leu768HisfsTer5), and a splice site mutation (c.2318+1G-A; 618704.0002) in intron 22, causing aberrant splicing that results in in-frame skipping of exon 22 with deletion of 31 amino acid residues (Cys743_Arg773del). Their unaffected parents were each heterozygous for one of the mutations, neither of which was found in the gnomAD database. Immunofluorescence analysis of patient ciliated cells revealed absence of CFAP221. Despite a normal ciliary ultrastructure and vigorous ciliary activity with only a slightly reduced beat frequency compared to control cilia, waveform analysis revealed that CFAP221-deficient cilia beat in a slightly circular pattern that, when measured as the maximum deviation from a linear beat, was a highly significant difference compared to control cilia.
For discussion of the c.2318+1G-A mutation (c.2318+1G-A, NM_001271049.2) in intron 22 of the CFAP221 gene, causing aberrant splicing and resulting in in-frame skipping of exon 22 with deletion of 31 amino acid residues (Cys743_Arg773del), that was found in compound heterozygous state in 3 French Canadian sibs with primary ciliary dyskinesia (CILD55; 279000) by Bustamante-Marin et al. (2020), see 618704.0001.
In a 39-year-old German woman (OP-2697) with primary ciliary dyskinesia (CILD55; 279000), Wohlgemuth et al. (2024) identified homozygosity for a 1-bp duplication (c.1641dup, NM_001170574.2) in the CFAP221 gene, causing a frameshift predicted to result in a premature termination codon (Asn548GlnfsTer6).
In an 18-year-old Polish man with primary ciliary dyskinesia, Rabiasz et al. (2025) identified homozygosity for the c.1641dup mutation in exon 16 of the CFAP221 gene. His unaffected parents and an unaffected brother were heterozygous for the duplication, which was not found in 630 Polish controls but was present at low minor allele frequency (0.0001441) in the gnomAD database. RT-PCR analysis of CFAP221 mRNA revealed lack of products in the proband's cDNA, and Western blot analysis confirmed complete absence of CFAP221 protein in patient nasal epithelial cells.
In a 42-year-old Japanese man with primary ciliary dyskinesia and infertility due to obstructive azoospermia (CILD55; 279000), Ito et al. (2025) identified compound heterozygosity for deletions in the CFAP221 gene: a 4-bp deletion (c.1465_1468del, NM_001271049.2) in exon 15, causing a frameshift predicted to result in a premature termination codon (Lys489ArgfsTer4), and an 18,187-bp deletion (chr2:119,624,023_119,642,209) spanning exons 15 to 21 (618704.0005)
For discussion of the 18,187-bp deletion (chr2:119,624,023-119,642,209) spanning exons 15 to 21 of the CFAP221 gene that was found in compound heterozygous state in a 42-year-old Japanese man with primary ciliary dyskinesia and infertility due to obstructive azoospermia (CILD55; 279000) by Ito et al. (2025), see 618704.0004.
Bustamante-Marin, X. M., Shapiro, A., Sears, P. R., Charng, W. L., Conrad, D. F., Leigh, M. W., Knowles, M. R., Ostrowski, L. E., Zariwala, M. A. Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia. J. Hum. Genet. 65: 175-180, 2020. [PubMed: 31636325] [Full Text: https://doi.org/10.1038/s10038-019-0686-1]
DiPetrillo, C. G., Smith, E. F. Pcdp1 is a central apparatus protein that binds Ca(2+)-calmodulin and regulates ciliary motility. J. Cell Biol. 189: 601-612, 2010. [PubMed: 20421426] [Full Text: https://doi.org/10.1083/jcb.200912009]
DiPetrillo, C. G., Smith, E. F. The Pcdp1 complex coordinates the activity of dynein isoforms to produce wild-type ciliary motility. Molec. Biol. Cell 22: 4527-4538, 2011. [PubMed: 21998195] [Full Text: https://doi.org/10.1091/mbc.E11-08-0739]
Finn, R., Evans, C. C., Lee, L. Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in PCDP1 and SPEF2. Neuroscience 277: 552-567, 2014. [PubMed: 25073043] [Full Text: https://doi.org/10.1016/j.neuroscience.2014.07.029]
Ito, M., Morimoto, K., Ohashi, M., Wakabayashi, K., Miyabayashi, A., Yamada, H., Hijikata, M., Keicho, N. Primary ciliary dyskinesia due to compound heterozygous variants in CFAP221 with obstructive azoospermia: Young's syndrome may be a phenotype of primary ciliary dyskinesia. Intern. Med. 64: 423-428, 2025. [PubMed: 38960684] [Full Text: https://doi.org/10.2169/internalmedicine.3978-24]
Lee, L., Campagna, D. R., Pinkus, J. L., Mulhern, H., Wyatt, T. A., Sisson, J. H., Pavlik, J. A., Pinkus, G. S., Fleming, M. D. Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1. Molec. Cell. Biol. 28: 949-957, 2008. [PubMed: 18039845] [Full Text: https://doi.org/10.1128/MCB.00354-07]
Rabiasz, A., Bukowy-Bieryllo, Z., Kazmierczak, P., Przystalowska-Maciola, H., Mikos, M., Wojsyk-Banaszak, I., Zietkiewicz, E. A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia. Biochim. Biophys. Acta Molec. Basis Dis. 1871: 167855, 2025. [PubMed: 40250778] [Full Text: https://doi.org/10.1016/j.bbadis.2025.167855]
Shen, G., Tian, E., Jiang, C., Tian, Y., Zhang, Y., Wang, X., Gu, J., Shen, Y., Geng, F. Establishing the causative link between CFAP221 variants and asthenoteratozoospermia in humans. J. Assist. Reprod. Genet. 42: 1975-1987, 2025. [PubMed: 40272718] [Full Text: https://doi.org/10.1007/s10815-025-03472-y]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/17/2019.
Wohlgemuth, K., Hoersting, N., Koenig, J., Loges, N. T., Raidt, J., George, S., Cindric, S., Schramm, A., Biebach, L., Lay, S., Dougherty, G. W., Olbrich, H., Pennekamp, P., Dworniczak, B., Omran, H. Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus. Europ. Resp. J. 64: 2400790, 2024. [PubMed: 39362668] [Full Text: https://doi.org/10.1183/13993003.00790-2024]