Alternative titles; symbols
HGNC Approved Gene Symbol: KATNIP
Cytogenetic location: 16p12.1 Genomic coordinates (GRCh38) : 16:27,550,144-27,780,344 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.1 | Joubert syndrome 26 | 616784 | Autosomal recessive | 3 |
The KATNIP gene encodes a microtubule-associated ciliary base protein that appears to regulate microtubule stability (summary by Sanders et al., 2015).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) isolated a partial KIAA0556 clone. The 1,081-amino acid sequence shares weak similarity with human collagen alpha-2(VIII) (COL8A2; 120252). RT-PCR detected variable KIAA0556 expression in all 14 human tissues examined, with highest expression in lung and lowest expression in skeletal muscle and spleen. SDS-PAGE revealed that KIAA0556 had an apparent molecular mass of more than 100 kD.
In human retinal pigmentary epithelial cells, Sanders et al. (2015) found expression of the KIAA0556 gene at the ciliary base, the axoneme, and the ciliary tip. In high-expressing cells, the protein also localized to the cytoplasm, where it appeared to decorate filamentous cytoskeletal structures. In C. elegans, there was expression of the Kiaa0556 ortholog in most ciliated cells, where it localized to the ciliary base and axoneme. These findings indicated that it is a highly conserved protein.
By radiation hybrid analysis, Nagase et al. (1998) mapped the KIAA0556 gene to chromosome 16. Gross (2015) mapped the KIAA0556 gene to chromosome 16p12.1 based on an alignment of the KIAA0556 sequence (GenBank AB011128) with the genomic sequence (GRCh38).
By overexpressing KIAA0556 in retinal epithelial cells, Sanders et al. (2015) found that the protein colocalized with acetylated alpha-tubulin signals and bound directly to microtubules, reflecting increased stabilization of cytoplasmic microtubules. Tandem affinity purification studies showed that KIAA0556 interacts with various katanin subunits (see, e.g., KATNA1, 606696), including KATNBL1 (616235). In C. elegans, KIAA0056 regulated ciliary A-tubule number and genetically interacted with an ARL13B (608922) ortholog to control cilium integrity.
In 3 sibs, born of consanguineous Saudi Arabian parents, with Joubert syndrome-26 (JBTS26; 616784), Sanders et al. (2015) identified a homozygous truncating mutation in the KIAA0556 gene (Q892X; 616650.0001). The mutation was found by exome sequencing and segregated with the disorder in the family.
In 2 brothers, born of first-cousin Indian parents (family 1015), with JBTS26, Roosing et al. (2016) identified homozygosity for a frameshift mutation in the KIAA0556 gene (616650.0002). The mutation segregated with the disorder in the family.
Sanders et al. (2015) found that homozygous Kiaa0556-null mice showed a variable hydrocephalus phenotype with enlargement of the ventricles resulting from a block of cerebrospinal fluid flow in the cerebral aqueduct. However, detailed analysis showed no gross defects in ventricular ependymal cilium structure or motility. Disruption of the Kiaa0556 ortholog in C. elegans resulted in grossly normal ciliary structure, function, and transport, but ultrastructural analysis showed significant microtubule defects. Studies in C. elegans indicated that KIAA0556 interacts with an ARL13B (608922) ortholog to control cilium integrity.
In 3 children, born of consanguineous parents of Saudi Arabian origin, with Joubert syndrome-26 (JBTS26; 616784), Sanders et al. (2015) identified a homozygous c.2674C-T transition (c.2674C-T, NM_015202.2) in the KIAA0556 gene, resulting in a gln892-to-ter (Q892X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in 615 control exomes. Patient cells showed near absence of the mutant transcript, consistent with nonsense-mediated mRNA decay and a complete loss of function. Patient-derived fibroblasts showed a significant reduction in the number of ciliated cells compared to controls, and the cilia that were present were abnormally long.
By whole-exome sequencing in 2 brothers, born of first-cousin Indian parents (family 1015), with Joubert syndrome-26 (JBTS26; 616784), Roosing et al. (2016) identified homozygosity for a single basepair deletion, c.4420del (chr16.17,786,375del, GRCh37), in the KIAA056 gene, predicting a frameshift and a premature stop codon (Met1474CysfsTer11) and nonsense mediated mRNA decay. The mutation segregated with the disorder in the family. The variant was not reported in the Exome Variant Server, ExAC, or 1000 Genomes Project databases. Knockdown of the single kiaa0556 ortholog in zebrafish resulted in morphants with curly tails, small head size, and perithoracic and abdominal edema. This phenotype could be rescued by wildtype human KIAA0556 mRNA.
Gross, M. B. Personal Communication. Baltimore, Md. 11/18/2015.
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Roosing, S., Rosti, R. O., Rosti, B., de Vrieze, E., Silhavy, J. L., van Wijk, E., Wakeling, E., Gleeson, J. G. Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. Hum. Genet. 135: 919-921, 2016. [PubMed: 27245168] [Full Text: https://doi.org/10.1007/s00439-016-1689-z]
Sanders, A. A. W. M., de Vrieze, E., Alazami, A. M., Alzahrani, F., Malarkey, E. B., Sorusch, N., Tebbe, L., Kuhns, S., van Dam, T. J. P., Alhashem, A., Tabarki, B., Lu, Q., and 20 others. KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome. Genome Biol. 16: 293, 2015. Note: Electronic Article. [PubMed: 26714646] [Full Text: https://doi.org/10.1186/s13059-015-0858-z]