HGNC Approved Gene Symbol: DNAAF6
Cytogenetic location: Xq22.3 Genomic coordinates (GRCh38): X:107,206,611-107,244,247 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.3 | Ciliary dyskinesia, primary, 36, X-linked | 300991 | X-linked recessive | 3 |
Based on experiments in mice, PIH1D3 is predicted to have a role in cytoplasmic assembly of axonemal dynein (see 603332) in sperm (Dong et al., 2014).
Dong et al. (2014) cloned mouse Pih1d3. The deduced protein is made up almost entirely of a PIH1 domain. RT-PCR analysis detected Pih1d3 in mouse testis only. Database analysis suggested that human PIH1D3 is also expressed exclusively in testis. In situ hybridization and immunohistochemical analysis detected Pih1d3 expression beginning in mouse pachytene spermatocytes at 5 weeks of age, and expression was detected in pachytene and diplotene spermatocytes of adult mice. It was not detected in spermatids or mature sperm.
Paff et al. (2017) stated that the PIH1D3 gene contains 8 exons and spans approximately 38 kb.
Hartz (2014) mapped the PIH1D3 gene to chromosome Xq22.3 based on an alignment of the PIH1D3 sequence (GenBank AI147427) with the genomic sequence (GRCh38).
Dong et al. (2014) found that mouse Pih1d3 interacted with an intermediate chain of the outer dynein arm (Dnaic2) and with Hsp70 (see 140550) and Hsp90 (see 140571).
In yeast 2-hybrid immunoprecipitation studies, Paff et al. (2017) found that PIH1D3 interacted with the axoneme assembly factors DNAAF2 (612517) and DNAAF4 (DYX1C1; 608706). The findings suggested that PIH1D3 is involved in dynein arm assembly and/or is important in facilitating assembly enabled by these other DNAAFs.
In 2 brothers and their maternal uncle with X-linked primary ciliary dyskinesia-36 (CILD36; 300991), Paff et al. (2017) identified a hemizygous frameshift mutation in exon 6 of the PIH1D3 gene (300933.0001). An unrelated male patient with CILD36 carried a different hemizygous truncating mutation (300933.0002) that occurred de novo. The patients were part of a larger cohort of 75 individuals with CILD who underwent targeted exome sequencing of a panel of 310 genes. Direct sequencing of the PIH1D3 gene in 40 additional males with PCD with ODA or combined ODA/IDA defects did not identify any additional mutations. Cilia in patient respiratory epithelial cells and sperm flagella showed absence of type 1 and type 2 outer dynein arms and greatly reduced or absent inner dynein arms in ciliary axonemes. The findings were consistent with a loss-of-function effect.
Dong et al. (2014) found that Pih1d3 -/- mice were born at the expected mendelian frequency and showed no overt phenotype. However, Pih1d3 -/- males were sterile due to immobility and fragility of sperm. Pih1d3 -/- females showed normal fertility. Outer dynein arms were almost entirely missing from Pih1d3 -/- sperm, and inner dynein arms were lost in some, but not all, mutant sperm. Mutant sperm showed reduced content of inner and outer dynein arm proteins. Dong et al. (2014) concluded that Pih1d3 is required for cytoplasmic preassembly of axonemal dyneins in mouse sperm.
In 2 brothers and their maternal uncle (family PCD-10) with X-linked primary ciliary dyskinesia-36 (CILD36; 300991), Paff et al. (2017) identified a hemizygous 7-bp deletion (c.357_363del, NM_001169154.1) in the PIH1D3 gene, predicted to result in a frameshift and premature termination (Val120LeufsTer6). The mutation, which was found by targeted exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Analysis of patient cells showed 2 abnormal transcripts: one that included the deletion in exon 6 and another that skipped exon 6. Each mutant transcript altered the reading frame to introduce premature termination in exon 6 and exon 8, respectively, yielding truncated proteins of 125 and 181 residues, respectively. The normal full-length protein is 214 residues. Only 1 of the transcripts appeared to be subject to nonsense-mediated mRNA decay. Western blot analysis of patient respiratory epithelial cells showed absence of the PIH1D3 protein, consistent with a loss of function.
In a man (patient OP-1899) with primary ciliary dyskinesia-36 (CILD36; 300991), Paff et al. (2017) identified a de novo hemizygous c.355C-T transition (c.355C-T, NM_001169154.1) in exon 6 of the PIH1D3 gene, resulting in a gln119-to-ter (Q119X) substitution. The mutation, which was found by targeted exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The mutation was predicted to result in a loss of function.
Dong, F., Shinohara, K., Botilde, Y., Nabeshima, R., Asai, Y., Fukumoto, A., Hasegawa, T., Matsuo, M., Takeda, H., Shiratori, H., Nakamura, T., Hamada, H. Pih1d3 is required for cytoplasmic preassembly of axonemal dynein in mouse sperm. J. Cell Biol. 204: 203-213, 2014. [PubMed: 24421334] [Full Text: https://doi.org/10.1083/jcb.201304076]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/7/2014.
Paff, T., Loges, N. T., Aprea, I., Wu, K., Bakey, Z., Haarman, E. G., Daniels, J. M. A., Sistermans, E. A., Bogunovic, N., Dougherty, G. W., Hoben, I. M., Grosse-Onnebrink, J., Matter, A., Olbrich, H., Werner, C., Pals, G., Schmidts, M., Omran, H., Micha, D. Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with outer and inner dynein arm defects. Am. J. Hum. Genet. 100: 160-168, 2017. [PubMed: 28041644] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.019]