HGNC Approved Gene Symbol: DNAI2
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:74,274,234-74,314,884 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Ciliary dyskinesia, primary, 9, with or without situs inversus | 612444 | Autosomal recessive | 3 |
Using a candidate gene approach, Pennarun et al. (1999) identified the DNAI1 gene (604366) and found it to be mutant in patients with primary ciliary dyskinesia (CILD1; 244400). Using the same approach, Pennarun et al. (2000) identified the DNAI2 gene, the human ortholog of Chlamydomonas IC69. The DNAI2 gene encodes a deduced 605-amino acid protein containing 5 WD-40 repeats and several putative phosphorylation sites. Northern blot analysis revealed high expression of an approximately 2.4-kb DNAI2 transcript in trachea and testis.
Pennarun et al. (2000) determined that the DNAI2 contains 14 exons.
By screening a panel of 24 hybrid somatic cell lines by PCR and by FISH, Pennarun et al. (2000) mapped the DNAI2 gene to 17q25.
By immunostaining, Loges et al. (2008) detected DNAI2 in assembled outer dynein arm complexes throughout all analyzed respiratory ciliary axonemes and sperm flagella. Further studies indicated that DNAH5 (603335) is essential for correct assembly of DNAI2 in outer dynein complexes.
In 3 patients with primary ciliary dyskinesia-9 (CILD9; 612444), Loges et al. (2008) identified different homozygous mutations in the DNAI2 gene (605483.0001-605483.0003).
In 3 individuals of Ashkenazi Jewish descent with CILD9, Knowles et al. (2013) identified a homozygous truncating mutation in the DNAI2 gene (W453X; 605483.0004). The mutation was identified by exome sequencing; haplotype analysis indicated a founder effect.
Exclusion Studies
Pennarun et al. (2000) evaluated the possible involvement of the DNAI2 gene in a CILD population with absent outer dynein arms. They found no mutation in the DNAI2 coding sequence of the 12 patients investigated. However, they identified 10 intragenic polymorphic sites and an EcoRI RFLP, allowing the exclusion of DNAI2 in 3 consanguineous families.
In 2 affected members of an Iranian Jewish kindred with primary ciliary dyskinesia-9 (CILD9; 612444), Loges et al. (2008) identified a homozygous G-to-A transition in intron 11 of the DNAI2 gene, resulting in the skipping of exon 11 and the loss of 49 amino acids. Two additional family members who also had situs inversus had the same homozygous mutation.
In a Hungarian patient with primary ciliary dyskinesia with situs inversus (CILD9; 612444), Loges et al. (2008) identified a homozygous T-to-G transversion in intron 3 of the DNAI2 gene, resulting in the skipping of exon 4 and premature protein truncation.
In a German patient with primary ciliary dyskinesia with situs inversus (CILD9; 612444), Loges et al. (2008) identified a homozygous 787C-T transition in exon 7 of the DNAI2 gene, resulting in an arg263-to-ter (R263X) substitution.
In 3 individuals of Ashkenazi Jewish descent with primary ciliary dyskinesia-9 (CILD9; 612444), Knowles et al. (2013) identified a homozygous 1304G-A transition in exon 10 of the DNAI2 gene, resulting in a trp453-to-ter (W453X) substitution. The mutation was identified by exome sequencing. Haplotype analysis indicated a founder effect. Respiratory epithelial cells showed ciliary outer dynein arm defects. The patients had neonatal respiratory distress, sinusitis, otitis, bronchiectasis, and decreased nasal nitric oxide; 2 had situs inversus.
Knowles, M. R., Leigh, M. W., Ostrowski, L. E., Huang, L., Carson, J. L., Hazucha, M. J., Yin, W., Berg, J. S., Davis, S. D., Dell, S. D., Ferkol, T. W., Rosenfeld, M., and 10 others. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am. J. Hum. Genet. 92: 99-106, 2013. [PubMed: 23261302] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.003]
Loges, N. T., Olbrich, H., Fenske, L., Mussaffi, H., Horvath, J., Fliegauf, M., Kuhl, H., Baktai, G., Peterffy, E., Chodhari, R., Chung, E. M. K., Rutman, A., and 10 others. DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. Am. J. Hum. Genet. 83: 547-558, 2008. [PubMed: 18950741] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.001]
Pennarun, G., Chapelin, C., Escudier, E., Bridoux, A.-M., Dastot, F., Cacheux, V., Goossens, M., Amselem, S., Duriez, B. The human dynein intermediate chain 2 gene (DNAI2): cloning, mapping, expression pattern, and evaluation as a candidate for primary ciliary dyskinesia. Hum. Genet. 107: 642-649, 2000. [PubMed: 11153919] [Full Text: https://doi.org/10.1007/s004390000427]
Pennarun, G., Escudier, E., Chapelin, C., Bridoux, A.-M., Cacheux, V., Roger, G., Clement, A., Goossens, M., Amselem, S., Duriez, B. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am. J. Hum. Genet. 65: 1508-1519, 1999. [PubMed: 10577904] [Full Text: https://doi.org/10.1086/302683]