Alternative titles; symbols
HGNC Approved Gene Symbol: DNAAF11
Cytogenetic location: 8q24.22 Genomic coordinates (GRCh38): 8:132,570,416-132,702,913 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.22 | Ciliary dyskinesia, primary, 19 | 614935 | Autosomal recessive | 3 |
Xue and Goldberg (2000) cloned mouse and human LRRC6, which they called LRTP, from testis cDNA libraries. The deduced 473-amino acid mouse protein contains 5 tandem leucine-rich repeats in its N-terminal end and several acidic regions in its C-terminal end. It also has 3 potential N-glycosylation sites and several putative phosphorylation sites. Northern blot analysis detected Lrtp expression in mouse testis only. Lrtp expression in mouse testis began 14 days after birth, concurrent with the appearance of mid-pachytene cells, and continued into adulthood. In situ hybridization detected Lrtp in seminiferous tubules, where it localized to the cytoplasm of pachytene cells in a ring-like distribution.
Morgan et al. (2005) cloned the Trypanosoma brucei ortholog of Lrtp. The deduced 383-amino acid trypanosome and 463-amino acid human proteins share 35% identity. In trypanosome, Lrtp was expressed at distal zones of basal bodies.
Kott et al. (2012) found expression of the LRRC6 gene in the testes and in nasal respiratory epithelial cells, typical of a cilia-associated gene. The expression was similar to that of DNAAF1 (613190), which shares similar protein domains.
Hartz (2012) mapped the LRRC6 gene to chromosome 8q24.22 based on an alignment of the LRRC6 sequence (GenBank BC027589) with the genomic sequence (GRCh37).
Using overexpression and RNA interference studies, Morgan et al. (2005) found that trypanosome Lrtp was important for faithful basal body duplication and flagellum biogenesis. Expression of excess Lrtp suppressed new flagellum assembly, whereas knockdown of Lrtp resulted in biogenesis of additional flagellar axonemes and paraflagellar rods that were intracellular. Aberrant basal body and flagellar biogenesis in Lrtp mutants also influenced cell size and cytokinesis.
Zariwala et al. (2013) found that ZMYND10 (607070) bound to LRRC6 in HEK293T and in human tracheal epithelial cells. These 2 proteins localized to both the basal body and the striated rootlet in Xenopus ciliated epithelial cells. Pull-down studies indicated that the C-terminal MYND domain of ZMYND10 was insufficient for interaction with the CS domain of LRRC6; rather, a C-terminal fragment that extended beyond the MYND domain was necessary for interaction between the 2 proteins. Similar studies using progressive truncating constructs of LRRC6 confirmed that the C-terminal CS domain of LRRC6 was sufficient for pull-down of ZMYND10. The C termini of the 2 proteins engaged in a protein-protein interaction that was abrogated by truncating mutations in either gene in patients with CILD. Immunofluorescence studies in rat trachea showed that ZMYND10 localized to sites proximal to the axoneme and colocalized to cytoplasmic puncta of varying sizes with SAS6 (609321), which is required for centriole assembly during ciliogenesis, and PCM1 (600299), which is a component of centriolar satellites. LRRC6 colocalized with ZMYND10 to the cytoplasmic puncta, but not to the axonemal domain. Coimmunoprecipitation studies showed that LRRC6 interacts with the dishevelled proteins DVL1 (601365), DVL2 (602151), and DVL3 (601368).
In 6 patients from 5 unrelated families of European descent with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified biallelic mutations in the LRRC6 gene (614930.0001-614930.0005). The first mutation was identified by homozygosity mapping and candidate gene analysis in an affected consanguineous family. The phenotype was characterized by chronic sinopulmonary infections, asthenospermia, and immotile cilia. All patients lacked both the inner and outer dynein arms in nasal respiratory epithelial cells or sperm flagella. Two patients had situs inversus. The patients with CILD19 accounted for 5 (10.6%) of 47 families with a CILD phenotype characterized by absence of both inner and outer dynein arms. Kott et al. (2012) speculated that the LRRC6 gene plays a role with other proteins in the cytoplasmic preassembly of dynein arms.
In 13 families with CILD19, Zariwala et al. (2013) identified 9 different homozygous or compound heterozygous mutations in the LRRC6 gene (see, e.g., 614930.0006 and 614930.0007). Five of the mutations were truncating. Patient respiratory samples showed defective ciliary outer and inner dynein arms on transmission electron microscopy, absence of the outer and inner arm proteins DNAH5 (603335) and DNALI1 (602135) from ciliary axonemes, and immotile cilia on video microscopy. Truncating mutations abrogated the interaction with ZMYND10 (607070), whereas missense mutations did not.
Serluca et al. (2009) found that the zebrafish ortholog of LRRC6, which they called seahorse (sea) or Lrrc6l, was expressed in all tissues containing motile cilia. They found that 2 mutations that caused curly tail and pronephric cysts in zebrafish were allelic mutations in the sea gene. One mutation resulted in protein truncation after a central coiled-coil region, and the other caused a missense substitution in leucine-rich repeat-4. Sea mutations had variable effects on cilia motility, as measured by fluid flow in Kupffer vesicles, but they did not alter early patterning of the pronephrose, had minimal effects on left-right patterning in visceral organ and on brain asymmetry, and had no effects on cilia structure. Morpholino-mediated knockdown of sea in zebrafish resulted in more severe defects in visceral organ placement and asymmetric gene expression.
Kavlie et al. (2010) found that mutation of the Drosophila ortholog of LRRC6, called 'touch insensitive larva B' (tilB), resulted in distinct ciliary defects. TilB mutant flies exhibited dysfunction in sperm flagella and ciliated dendrites of chordotonal organs that mediate hearing and larval touch sensitivity. TilB mutant axonemes showed defective architecture and lacked portions of dynein arms.
In 2 European sibs, born of consanguineous parents, with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified a homozygous 2-bp deletion (598_599delAA) in exon 5 of the LRRC6 gene, resulting in a frameshift and premature termination (Lys200GlufsTer3). The mutation was identified by homozygosity mapping followed by candidate gene analysis. The asymptomatic mother carried the mutation in the heterozygous state; DNA from the father was unavailable. The mutation was not found in several large control databases. Both patients had a chronic sinopulmonary syndrome with variable infertility and immotile cilia lacking both the inner and outer dynein arms. One had situs inversus. Subsequent analysis of 40 patients with CILD lacking both outer and inner dynein arms identified 1 patient who was homozygous for the 598_599delAA mutation and another who was compound heterozygous for 598_599delAA and a missense mutation (D146H; 614930.0005). Haplotype analysis of the allele carrying the 598_599delAA mutation supported a founder effect.
In a European male with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified compound heterozygosity for 2 truncating mutations in exon 5 of the LRRC6 gene: a 574C-T transition, resulting in a gln192-to-ter (Q193X) substitution, and a 1-bp duplication (576dupA; 614930.0003), resulting in a frameshift and premature termination (Glu193ArgfsTer4). The patient had a chronic sinopulmonary syndrome with asthenospermia and immotile cilia lacking the inner and outer dynein arms. LRRC6 was not detected in airway epithelial cells from this patient, whereas it was detected in controls. The findings were consistent with a loss-of-function pathogenic mechanism.
For discussion of the 1-bp duplication in the LRRC6 gene (576dupA) that was found in compound heterozygous state in a patient with primary ciliary dyskinesia-19 (CILD19; 614935) by Kott et al. (2012), see 614930.0002.
In a patient with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified a homozygous 220G-C transversion in exon 3 of the LRRC6 gene, resulting in an ala74-to-pro (A74P) substitution at a highly conserved residue in the third LRR motif. This patient had moderate respiratory symptoms with partial absence of the outer and inner dynein arms of nasal respiratory epithelial cells and immotile cilia; the phenotype was slightly milder compared to the CILD19 patients with truncating mutations on at least 1 allele.
In a European male with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified compound heterozygosity for 2 mutations in the LRRC6 gene: a 436G-C transversion in exon 5, resulting in an asp146-to-his (D146H) substitution at a highly conserved residue in the LRRcap, and a 2-bp deletion (598delAA; 614930.0001). The D146H mutation was predicted to affect protein conformation. The 436G-C mutation has been reported as a rare SNP (rs200321595) with a low allele frequency (0.00023). The patient had a chronic sinopulmonary syndrome, asthenospermia, and situs inversus associated with lack of the inner and outer ciliary dynein arms.
In affected individuals from 6 Asian Pakistani families with primary ciliary dyskinesia-19 (CILD19; 614935) with or without situs inversus, Zariwala et al. (2013) identified a homozygous 1-bp deletion in exon 5 of the LRRC6 gene (c.630delG), resulting in a frameshift and premature termination (Trp210CysfsTer12). The mutation was initially found by homozygosity mapping and whole-exome sequencing in a consanguineous family. All patients showed defective ciliary outer and inner dynein arms on transmission electron microscopy, and 1 patient studied by video microscopy had immotile cilia. The truncating mutation abrogated the interaction with ZMYND10 (607070).
In a Turkish patient with primary ciliary dyskinesia-19 (CILD19; 614935), Zariwala et al. (2013) identified a homozygous c.562C-T transition in exon 5 of the LRRC6 gene, resulting in a gln188-to-ter (Q188X) substitution. Patient respiratory samples showed defective ciliary outer dynein and inner dynein arms on transmission electron microscopy, absence of the outer and inner arm proteins DNAH5 (603335) and DNALI1 (602135) from ciliary axonemes, and immotile cilia on video microscopy. The truncating mutation abrogated the interaction with ZMYND10 (607070).
Hartz, P. A. Personal Communication. Baltimore, Md. 11/13/2012.
Kavlie, R. G., Kernan, M. J., Eberl, D. F. Hearing in Drosophila requires TilB, a conserved protein associated with ciliary motility. Genetics 185: 177-188, 2010. [PubMed: 20215474] [Full Text: https://doi.org/10.1534/genetics.110.114009]
Kott, E., Duquesnoy, P., Copin, B., Legendre, M., Dastot-Le Moal, F., Montantin, G., Jeanson, L., Tamalet, A., Papon, J.-F., Siffroi, J.-P., Rives, N., Mitchell, V., de Blic, J., Coste, A., Clement, A., Escalier, D., Toure, A., Escudier, E., Amselem, S. Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. Am. J. Hum. Genet. 91: 958-964, 2012. [PubMed: 23122589] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.003]
Morgan, G. W., Denny, P. W., Vaughan, S., Goulding, D., Jeffries, T. R., Smith, D. F., Gull, K., Field, M. C. An evolutionarily conserved coiled-coil protein implicated in polycystic kidney disease is involved in basal body duplication and flagellar biogenesis in Trypanosoma brucei. Molec. Cell. Biol. 25: 3774-3783, 2005. [PubMed: 15831481] [Full Text: https://doi.org/10.1128/MCB.25.9.3774-3783.2005]
Serluca, F. C., Xu, B., Okabe, N., Baker, K., Lin, S.-Y., Sullivan-Brown, J., Konieczkowski, D. J., Jaffe, K. M., Bradner, J. M., Fishman, M. C., Burdine, R. D. Mutations in zebrafish leucine-rich repeat-containing six-like affect cilia motility and result in pronephric cysts, but have variable effects on left-right patterning. Development 136: 1621-1631, 2009. [PubMed: 19395640] [Full Text: https://doi.org/10.1242/dev.020735]
Xue, J.-C., Goldberg, E. Identification of a novel testis-specific leucine-rich protein in humans and mice. Biol. Reprod. 62: 1278-1284, 2000. [PubMed: 10775177] [Full Text: https://doi.org/10.1095/biolreprod62.5.1278]
Zariwala, M. A., Gee, H. Y., Kurkowiak, M., Al-Mutairi, D. A., Leigh, M. W., Hurd, T. W., Hjeij, R., Dell, S. D., Chaki, M., Dougherty, G. W., Adan, M., Spear, P. C., and 46 others. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am. J. Hum. Genet. 93: 336-345, 2013. [PubMed: 23891469] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.007]