Alternative titles; symbols
HGNC Approved Gene Symbol: ZMYND10
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:50,341,112-50,345,732 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Ciliary dyskinesia, primary, 22 | 615444 | Autosomal recessive | 3 |
The ZMYND10 gene encodes a protein involved in motile ciliary function (Zariwala et al., 2013).
By physical cloning methodologies and bioinformatic computational analyses, Lerman and Minna (2000) identified a number of genes, including BLU, in a region of chromosome 3p21.3 that is associated with a putative lung cancer tumor suppressor gene. The deduced 440-amino acid conserved soluble cytoplasmic protein is 89% identical to the mouse protein and is somewhat homologous to the MTG/ETO family of transcription factors (see CBFA2T1; 133435). It contains a zinc knuckle motif. Northern blot analysis revealed expression of a 2.0-kb transcript limited to lung, with trace expression in kidney, liver, placenta, and brain; a shorter isoform was found to be expressed in testis. BLU was expressed in few lung cancer cell lines. Mutations were found in approximately 5% of cell lines tested, but none of the genes identified in the search had a high frequency of mutations. Lerman and Minna (2000) suggested that BLU is a candidate for functional tumor suppressor gene studies.
In mouse embryos, Moore et al. (2013) found expression of the Zmynd10 gene in the ciliated epithelial layers associated with nasal and lung epithelium, where motile cilia are located.
By genomic sequence analysis, Lerman and Minna (2000) determined that the BLU gene contains 12 exons and spans 4.7 kb. The testis isoform contains 11 exons.
By genomic sequence analysis, Lerman and Minna (2000) determined that the BLU gene resides in a 120-kb critical region for a lung cancer tumor suppressor gene on chromosome 3p21.3.
To evaluate the role of BLU in tumorigenesis, Agathanggelou et al. (2003) analyzed BLU promoter methylation status in tumor cell lines and detected promoter region hypermethylation in 39% of lung, 42% of breast, 50% of kidney, 86% of neuroblastoma, and 80% of nasopharyngeal tumor cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumor cell lines. Expression was recovered in tumor cell lines treated with 5-aza 2-deoxycytidine.
Zariwala et al. (2013) found that ZMYND10 bound to LRRC6 (614930) 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. In cellular studies, knockdown of ZMYND10 using shRNA was associated with decreased amounts of DNAH5 and DNALI1 mRNA, suggesting that ZMYND10 can regulate transcription of dynein proteins. Overall, the findings indicated that ZMYND10 has a role in motile cilia.
Moore et al. (2013) also found that ZMYND10 interacted with LRRC6.
In affected members of 14 families with primary ciliary dyskinesia-22 (CILD22; 615444) with or without situs inversus, Zariwala et al. (2013) identified 11 different homozygous or compound heterozygous mutations in the ZMYND10 gene (see, e.g., 607070.0001-607070.0004). The initial mutation was found by homozygosity mapping combined with whole-exome sequencing in an Israeli individual with situs inversus. The subsequent mutations were found by sequencing the ZMYND10 gene in 300 patients with CILD. Transmission electron microscopy of respiratory ciliary epithelial samples from affected individuals showed a lack of outer and inner dynein arms on the ciliary axonemes, and immunofluorescence studies showed absence of the inner-arm protein DNALI1 (602135) and the outer-arm protein DNAH5 (603335). Truncating mutations in ZMYND10 (see, e.g., 606070.0002 and 606070.0004) abrogated the interaction between ZMYND10 and LRRC6, whereas missense mutations did not.
Moore et al. (2013) identified biallelic mutations in the ZMYND10 gene (see, e.g., 607070.0001; 607070.0005-607070.0006) in 6 (16%) of 38 families with CILD characterized by inner and outer dynein arm defects on ultrastructural analysis of respiratory epithelial cells. The initial mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The mutations segregated with the disorder in the families. Most patients had a loss of inner and outer dynein arms from the cilia, but those with the missense mutation V16G (607070.0001) had an apparently intermediate phenotype with variable retention of the inner and outer dynein arms. Video microscopy of most patients showed cilia that were almost completely static, but 1 patient with the V16G mutation had cilia with a slowed and stiff beating pattern.
Zariwala et al. (2013) found that knockdown of the Zmynd10 gene in zebrafish caused ciliopathy phenotypes, including the appearance of 3 otoliths, kidney cysts, and dilated kidney tubules. Cilia in the kidney showed disorganized cilia bundles with either severely reduced beat amplitude or paralysis, and olfactory motile cilia were nearly completely paralyzed. Knockdown of Zmynd10 in Xenopus embryos caused a defect in ciliogenesis and a weaker flow.
Moore et al. (2013) found that the Drosophila Zmynd10 ortholog is highly expressed in the transcriptome of developing chordotonal sensory neurons, which have motile mechanosensory cilia. In adults, Zmynd10 was exclusively expressed in the testes. Drosophila homozygous for a loss-of-function Zmynd10 mutation showed uncoordinated locomotion due to defective proprioception as a result of malfunctioning chordotonal neurons. The mice were also infertile. Ultrastructural analysis of the chordotonal neuron cilium from mutant flies showed that the inner and outer dynein arms were reduced, although ciliogenesis appeared normal. Sperm from mutant flies were immotile and sperm flagella showed a partial loss of dynein arms, as well as axoneme splitting.
In a patient with primary ciliary dyskinesia-22 (CILD22; 615444) and situs inversus, Zariwala et al. (2013) identified a homozygous c.47T-G transversion in exon 1 of the ZMYND10 gene, resulting in a val16-to-gly (V16G) substitution at a conserved residue. Video microscopy of patient respiratory cells showed immotile cilia, and electron microscopy showed outer and inner dynein arm defects.
In 3 patients from 2 unrelated families of northern European descent with CILD22, Moore et al. (2013) identified a homozygous V16G (rs138815960) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The V16G variant was present in 6 of 4,300 European control exomes from the NHLBI Exome Sequencing Project Exome Variant Server, corresponding to a frequency of 0.000698; the variant was absent from 700 in-house control exomes. The clinical features were available for 1 of the homozygous patients. She had recurrent respiratory infections from birth, persistent rhinitis, recurrent otitis media, and bronchiectasis. Light microscopy of respiratory epithelial cells from this patient showed cilia with slowed frequency and stiff beat, and electron microscopy showed reduced, but not absent, inner and outer dynein arms. Two additional unrelated patients with CILD22 were compound heterozygous for V16G and another pathogenic mutation in the ZMYND10 gene (see, e.g., 607070.0006). Haplotype analysis suggested a founder effect among these patients. Transfection of the corresponding mutation (V14G) in Drosophila restored fertility in a mutant model, but not as fully as transfection with the wildtype protein. The findings suggested that the V16G allele may retain some function.
In a patient with primary ciliary dyskinesia (CILD22; 615444), Zariwala et al. (2013) identified a homozygous 1-bp deletion (c.300delC) in exon 3 of the ZMYND10 gene, resulting in a frameshift and premature termination (Phe101SerfsTer38). Video microscopy of patient respiratory cells showed immotile cilia, and electron microscopy showed outer and inner dynein arm defects.
In a Turkish patient, born of consanguineous parents, with primary ciliary dyskinesia (CILD22; 615444), Zariwala et al. (2013) identified a homozygous 1-bp duplication (c.486dupA) in exon 5 in the ZMYND10 gene, resulting in a frameshift and premature termination (Ser163IlefsTer20). Immunofluorescence studies showed decreases in DNAH5 (603335) and DNALI1 (602135), and video microscopy of patient respiratory cells showed immotile cilia.
In 2 unrelated patients of French and Hispanic origin, respectively, with primary ciliary dyskinesia (CILD22; 615444), Zariwala et al. (2013) identified a homozygous c.967C-T transition in exon 9 of the ZMYND10 gene, resulting in a gln323-to-ter (Q323X) substitution. Both patients had situs inversus and defects of the outer and inner dynein arms on electron microscopy. Video microscopy, which was done on 1 patient's respiratory cells, showed immotile cilia.
In a girl of northern European descent with primary ciliary dyskinesia (CILD22; 615444), Moore et al. (2013) identified compound heterozygous mutations in the ZMYND10 gene: a 2-bp deletion (c.589_590delTG), resulting in a frameshift and premature termination (Val198GlyfsTer13), and V16G (607070.0001). The patient had respiratory distress from birth, chronic cough, persistent rhinosinusitis, bronchiectasis, otitis media, and dextrocardia. Light microscopy of respiratory epithelial cells showed static cilia, and electron microscopy showed absence of the inner and outer dynein arms. The unaffected parents were heterozygous for 1 of the mutations. The mutation was present at a frequency of less than 0.01 in the 1000 Genomes Project database and was not found in 700 in-house control exomes.
In 2 sibs of northern European descent with primary ciliary dyskinesia (CILD22; 615444), Moore et al. (2013) identified a homozygous c.797T-C transition in the ZMYND10 gene, resulting in a leu266-to-pro (L266P) substitution at a conserved residue in an LxxLL motif. Both had recurrent respiratory infections, ciliary motility defects, and absence of the inner and outer dynein arms on electron microscopy. One had situs inversus. The mutation was present at a frequency of less than 0.01 in the 1000 Genomes Project database and was not found in 700 in-house control exomes. The unaffected parents were heterozygous for the mutation.
Agathanggelou, A., Dallol, A., Zochbauer-Muller, S., Morrissey, C., Honorio, S., Hesson, L., Martinsson, T., Fong, K. M., Kuo, M. J., Yuen, P. W., Maher, E. R., Minna, J. D., Latif, F. Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene 22: 1580-1588, 2003. [PubMed: 12629521] [Full Text: https://doi.org/10.1038/sj.onc.1206243]
Lerman, M. I., Minna, J. D. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. Cancer Res. 60: 6116-6133, 2000. [PubMed: 11085536]
Moore, D. J., Onoufriadis, A., Shoemark, A., Simpson, M. A., zur Lage, P. I., de Castro, S. C., Bartoloni, L., Gallone, G., Petridi, S., Woollard, W. J., Antony, D., Schmidts, M., and 19 others. Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. Am. J. Hum. Genet. 93: 346-356, 2013. [PubMed: 23891471] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.009]
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]