Alternative titles; symbols
HGNC Approved Gene Symbol: DNAAF1
Cytogenetic location: 16q24.1 Genomic coordinates (GRCh38): 16:84,145,308-84,177,920 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.1 | Ciliary dyskinesia, primary, 13 | 613193 | Autosomal recessive | 3 |
The DNAAF1 gene encodes a component of the microtubule outer dynein arm and appears to stabilize microtubule-based cilia and actin-based brush border microvilli (van Rooijen et al., 2008).
Freshour et al. (2007) cloned Chlamydomonas Oda7 and identified Oda7 orthologs in many other species, including human. The deduced Oda7 protein contains an N-terminal leucine-rich repeat (LRR).
By searching an EST database for sequences similar to zebrafish Lrrc50, van Rooijen et al. (2008) identified 2 splice variants of human LRRC50 that encode proteins initiated from different ATG codons in exons 1 and 3. The deduced proteins contain 637 and 725 amino acids, and both have 6 N-terminal LRR motifs, an LRR cap, a coiled-coil, and a nonconserved proline-rich domain. The sixth LRR partially overlaps the putative LRR cap. In situ hybridization of zebrafish showed that Lrcc50 was expressed in ciliated tissues throughout development, including dorsal forerunner cells during gastrulation and otic placode, pronephric duct, floorplate, neural tube, nose, and brain (diffusely) during later stages. Fluorescence-tagged LRRC50 localized to spindle poles of mitotic human embryonic kidney cells and MDCK canine kidney cells and to ciliary structures extending from the basal body of ciliated MDCK cells.
Loges et al. (2009) found expression of the Lrrc50 gene in mice at the embryonic node and in respiratory cells. Duquesnoy et al. (2009) found expression of LRRC50 in human adult trachea and testis.
Freshour et al. (2007) stated that mutations in the Oda7 gene in Chlamydomonas prevent axonemal outer row dynein assembly by blocking association of heavy chains and intermediate chains in the cytoplasm. They found that Oda7 interacted with both outer row dynein and I1 inner row dynein and formed a bridge between these 2 motors on the doublet surface. Freshour et al. (2007) concluded that Oda7 performs a structural link between inner and outer row dyneins.
Using RNA interference, van Rooijen et al. (2008) found that knockdown of LRRC50 reduced the apical brush border of polarized HK-2 human proximal tubule cells and reduced ciliary length in ciliated HK-2 cells.
Van Rooijen et al. (2008) determined that the LRRC50 gene contains 12 exons and spans 32.6 kb.
Van Rooijen et al. (2008) stated that the DNAAF1 gene maps to chromosome 16q24.1.
In 3 probands with primary ciliary dyskinesia associated with combined inner and outer dynein arm defects (CILD13; 613193), Loges et al. (2009) identified homozygous or compound heterozygous mutations in the LRRC50 gene (see, e.g., 613190.0001 and 613190.0002). One patient was homozygous for a truncating mutation, 1 was compound heterozygous for larger deletions involving LRRC50 and neighboring genes, and 1 was compound heterozygous for a deletion and truncation mutation. Functional analysis showed that LRRC50 deficiency resulted in disrupted assembly of DNAH5 (603335)- and DNAI2 (605483)-containing outer dynein arms, as well as DNALI1 (602135)-containing inner dynein arm complexes, resulting in loss of both arms and functionally immotile cilia in respiratory cells.
Duquesnoy et al. (2009) identified 6 different heterozygous defects in the LRRC50 gene (see, e.g., 613190.0003-613190.0004) in 3 unrelated patients with CILD13, as well as a homozygous mutation (L175R; 613190.0005) in 2 sibs with CILD13. All mutations led to a loss of function, and all patients had defects of both the inner and outer dynein arms.
Van Rooijen et al. (2008) developed a line of zebrafish with a mutation in the Lrcc50 gene. Mutant embryos showed a pronounced ventral body curve, and cilia of Kupffer vesicles, which are required to break bilateral symmetry in zebrafish, showed no motility. Mutant pronephric tubules showed cysts and reduced brush border with short microvilli. Homozygous mutants died during early larval stages with severe edema, likely due to pronephric disease progression. Glomerular filtration was normal, but pronephric fluid flow was slower than normal. Electron microscopy of pronephric mutant cilia revealed ultrastructural irregularities, and some axonemes completely lacked all dynein arms or had misplaced inner dynein arms. Van Rooijen et al. (2008) concluded that LRRC50 is involved in stabilizing ciliary architecture.
In a mouse mutant cell line with hydrocephalus, laterality defects, and sinusitis, Ha et al. (2016) identified homozygosity for a donor splice site mutation at exon 4 in the Dnaaf1 gene, predicted to result in a large internal deletion or premature termination. Most of the mutants were severely runted compared with littermates and frequently died during the second postnatal week. The authors suggested that the Dnaaf1 mutation caused defects in motile cilia function.
In a 16-year-old German patient with primary ciliary dyskinesia-13 (CILD13; 613193) and situs inversus totalis, Loges et al. (2009) identified a homozygous 1-bp insertion (1349insC) in the LRRC50 gene, resulting in premature protein truncation. The unaffected parents were heterozygous for the mutation. The patient had both inner and outer dynein arm defects and severe bronchiectasis.
In a patient with primary ciliary dyskinesia-13 (CILD13; 613193), situs inversus totalis, and destructive lung disease, Loges et al. (2009) identified a heterozygous 811C-T transition in the LRRC50 gene, resulting in an arg271-to-ter (R271X) substitution. Further analysis of the patient's DNA also showed a large 220-kb heterozygous deletion including the 5-prime untranslated region and the first exon of the LRRC50 gene, as well as 6 neighboring genes. There was a marked reduction in inner and outer dynein arm motility.
In a girl with primary ciliary dyskinesia-13 (CILD13; 613193), Duquesnoy et al. (2009) identified compound heterozygosity for 2 truncating mutations in the LRRC50 gene: a 792C-A transversion in exon 6, resulting in a tyr264-to-ter (Y264X) substitution, and a 1-bp duplication (508dupG; 613190.0004) in exon 4, resulting in a frameshift and premature protein truncation. The patient had situs inversus, sterility, and airway disease with bronchitis, sinusitis, and bronchiectasis. The cilia showed no beat, and transmission electron microscopy showed absence of both inner and outer dynein arms.
For discussion of the 1-bp duplication in the DNAAF1 gene (508dupG) that was found in a patient with primary ciliary dyskinesia-13 (CILD13; 613193) by Duquesnoy et al. (2009), see 613190.0003.
In 2 brothers, born of consanguineous parents, with primary ciliary dyskinesia-13 (CILD13; 613193), Duquesnoy et al. (2009) identified a homozygous C-T transition in exon 4 of the LRRC50 gene, resulting in a leu175-to-arg (L175R) substitution in the third LRR domain. Although neither boy had situs inversus, both had airway disease with bronchitis, sinusitis, otitis, and bronchiectasis necessitating lobectomy. Respiratory cilia showed no beat, and transmission electron microscopy showed absence of both inner and outer dynein arms. The unaffected parents were heterozygous for the mutation. The mutation occurred in an invariant residue in LRRC50 orthologs, and was predicted to contribute to the hydrophobic core of the LRR arcs. In vitro functional expression assays in flagellated protists showed that the L175R-mutant protein resulted in flagellar hypomotility and decrease or loss of inner and outer dynein arms. The findings suggested that functioning LRRC50 played a role in cytoplasmic preassembly of dynein arms.
Duquesnoy, P., Escudier, E., Vincensini, L., Freshour, J., Bridoux, A.-M., Coste, A., Deschildre, A., de Blic, J., Legendre, M., Montantin, G., Tenreiro, H., Vojtek, A.-M., Loussert, C., Clement, A., Escalier, D., Bastin, P., Mitchell, D. R., Amselem, S. Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. Am. J. Hum. Genet. 85: 890-896, 2009. [PubMed: 19944405] [Full Text: https://doi.org/10.1016/j.ajhg.2009.11.008]
Freshour, J., Yokoyama, R., Mitchell, D. R. :Chlamydomonas flagellar outer row dynein assembly protein Oda7 interacts with both outer row and I1 inner row dyneins. J. Biol. Chem. 282: 5404-5412, 2007. [PubMed: 17194703] [Full Text: https://doi.org/10.1074/jbc.M607509200]
Ha, S., Lindsay, A. M., Timms, A. E., Beier, D. R. Mutations in Dnaaf1 and Lrrc48 cause hydrocephalus, laterality defects, and sinusitis in mice. G3 (Bethesda) 6: 2479-2487, 2016. [PubMed: 27261005] [Full Text: https://doi.org/10.1534/g3.116.030791]
Loges, N. T., Olbrich, H., Becker-Heck, A., Haffner, K., Heer, A., Reinhard, C., Schmidts, M., Kispert, A., Zariwala, M. A., Leigh, M. W., Knowles, M. R., Zentgraf, H., Seithe, H., Nurnberg, G., Nurnberg, P., Reinhardt, R., Omran, H. Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am. J. Hum. Genet. 85: 883-889, 2009. [PubMed: 19944400] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.018]
van Rooijen, E., Giles, R. H., Voest, E. E., van Rooijen, C., Schulte-Merker, S., van Eeden, F. J. LRRC50, a conserved ciliary protein implicated in polycystic kidney disease. J. Am. Soc. Nephrol. 19: 1128-1138, 2008. [PubMed: 18385425] [Full Text: https://doi.org/10.1681/ASN.2007080917]