Alternative titles; symbols
HGNC Approved Gene Symbol: KIAA0586
Cytogenetic location: 14q23.1 Genomic coordinates (GRCh38): 14:58,427,400-58,562,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.1 | Joubert syndrome 23 | 616490 | Autosomal recessive | 3 |
| Short-rib thoracic dysplasia 14 with polydactyly | 616546 | Autosomal recessive | 3 |
The KIAA0586 gene encodes the homolog of the mouse and chicken TALPID3 gene, which is a centrosomal protein required for ciliogenesis and hedgehog (SHH; 600725) signaling (summary by Bachmann-Gagescu et al., 2015).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1998) cloned KIAA0586. The deduced protein contains 1,533 amino acids. RT-PCR detected moderate expression in kidney only.
Davey et al. (2006) identified KIAA0586 orthologs in vertebrates only. In chicken, the protein localized to the cytoplasm.
Alby et al. (2015) tested KIAA0586 expression in various tissues at different human developmental stages and observed specific exon 2-containing transcripts as early as 6 weeks' gestation (Carnegie stage 16). The KIAA0586 transcripts were ubiquitously expressed during fetal development and persisted postnatally in all adult tissues tested.
By radiation hybrid analysis, Nagase et al. (1998) mapped the KIAA0586 gene to chromosome 14.
Joubert Syndrome 23
In affected individuals from 9 unrelated families with Joubert syndrome-23 (JBTS23; 616490), Bachmann-Gagescu et al. (2015) identified homozygous or compound heterozygous mutations in the KIAA0586 gene (see, e.g., 610178.0001-610178.0005). Mutations in the first patient were found by whole-exome sequencing; biallelic mutations in 8 additional families were found by sequencing the exons of the KIAA0586 gene in a cohort of 366 additional families with the disorder. Overall, biallelic mutations were found in 9 (2.5%) of 366 families. Seven additional patients had heterozygous mutations in the KIAA0586 gene. One recurrent truncating mutation (610178.0001) was found in 7 of the 9 families. Functional studies of the variants were not performed. The phenotype was relatively mild and homogeneous, consisting mainly of neurologic features, such as delayed development, abnormal eye movements, and the molar tooth sign on brain imaging. Only 1 patient had polydactyly; none had retinal, renal, or liver involvement.
Short-Rib Thoracic Dysplasia 14 with Polydactyly
By targeted next-generation sequencing of candidate ciliary genes in a consanguineous Lebanese family in which 2 fetuses exhibited severe hydrocephaly, polydactyly, and skeletal abnormalities (SRTD14; 616546), Alby et al. (2015) identified homozygosity for a nonsense mutation in the KIAA0586 gene (S77X; 610178.0006) that segregated with disease. Additional next-generation sequencing of ciliary genes in 150 individuals with lethal ciliopathies and various combinations of brain and skeletal abnormalities identified 3 patients from 3 unrelated Eastern European families with cerebral anomalies, polydactyly, and long-bone shortening, including short ribs, who were all homozygous for the same splice site variant in KIAA0586 (610178.0007). Haplotype analysis in the Romanian, Hungarian, and Kosovan families was consistent with a common ancestor, estimated to hve lived 16 generations (480 years) earlier. Defective ciliogenesis as well as abnormal response to SHH (600725)-signaling activation was observed in patient cells.
Talpid-3 is a chicken mutant with abnormal limb patterning and malformations in other regions of the embryo that depend on hedgehog (SHH; 600725) signaling. Davey et al. (2006) determined that talpid-3 is due to a frameshift mutation in the chicken ortholog of KIAA0586, leading to a truncated protein.
In a 5-year-old patient (UW176-3) with Joubert syndrome-23 (JBTS23; 616490), Bachmann-Gagescu et al. (2015) identified compound heterozygous mutations in the KIAA0586 gene: a 1-bp deletion (c.428delG, NM_001244189.1), resulting in a frameshift and premature termination (Arg143LysfsTer4), and a G-to-C transversion (c.1413-1G-C; 610178.0002), resulting in a splice site mutation. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family and were filtered against the Exome Variant Server database. Direct sequencing of the KIAA0586 gene in a cohort of 366 families with Joubert syndrome found the c.428delG mutation in 6 additional patients: 1 was homozygous for the mutation, whereas the others carried it in compound heterozygosity with another pathogenic mutation (see, e.g., 610178.0003-610178.0004). The c.428delG mutation was found at a frequency of 0.39% in the ExAC and Exome Variant Server databases, but only as a heterozygous variant. Functional studies of the variants were not performed.
For discussion of the c.1413-1G-C mutation (c.1413-1G-C, NM_001244189.1) in the KIAA0586 gene that was found in compound heterozygous state in a patient with Joubert syndrome-23 (JBTS23; 616490) by Bachmann-Gagescu et al. (2015), see 610178.0001.
In a patient (UW175-3) with Joubert syndrome-23 (JBTS23; 616490), Bachmann-Gagescu et al. (2015) identified compound heterozygous mutations in the KIAA0586 gene: a c.1159C-T transition (c.1159C-T, NM_001244189.1), resulting in a gln387-to-ter (Q387X) substitution, and c.428delG (610178.0001). Functional studies of the variants were not performed.
In a patient (UW178-3) with Joubert syndrome-23 (JBTS23; 616490), Bachmann-Gagescu et al. (2015) identified compound heterozygous mutations in the KIAA0586 gene: a 2-bp deletion (c.863_864delAA, NM_001244189.1), resulting in a frameshift and premature termination (Gln288ArgfsTer7), and c.428delG (610178.0001). Functional studies of the variants were not performed.
In a patient (UW180-3) with Joubert syndrome-23 (JBTS23; 616490), Bachmann-Gagescu et al. (2015) identified a homozygous c.1697A-T transversion (c.1697A-T, NM_001244189.1) in the KIAA0586 gene, resulting in an asp566-to-val (D566V) substitution. Functional studies of the variant were not performed.
In a fetus with severe hydrocephaly, polydactyly, and skeletal abnormalities (SRTD14; 616546) from a consanguineous Lebanese family in which there were multiple early spontaneous abortions, Alby et al. (2015) identified homozygosity for a c.230C-G transversion (c.230C-G, NM_001244189.1) in exon 2 of the KIAA0536 gene, resulting in a ser77-to-ter (S77X) substitution. The mutation segregated with disease in the family and was not found in 300 Lebanese control chromosomes or in the dbSNP, Exome Variant Server, or ExAC databases. RT-PCR analysis of patient mRNA showed total absence of transcript containing KIAA0586 exon 2.
In affected members of 3 unrelated Eastern European (Romanian, Hungarian, and Kosovan) families who exhibited cerebral anomalies, polydactyly of the hands and feet, and long-bone shortening, including short ribs (SRTD14; 616546), Alby et al. (2015) identified homozygosity for a c.1815G-A transition (c.1815G-A, NM_001244189.1) involving the last base of exon 14 in the KIAA0586 gene, predicted to abolish the intron 14 donor splice site. RT-PCR analysis of mRNA from the 2 Romanian patients confirmed the presence of a unique transcript lacking exon 14, predicted to cause a frameshift resulting in a premature termination codon. The mutation segregated with disease in each family and was not found in the dbSNP, Exome Variant Server, or ExAC databases. Induction of ciliogenesis in patient fibroblasts showed that only 20% presented with cilia at 48 hours compared to 60% of control fibroblasts, and staining for centriolar proteins in patient cells showed an abnormal extended pattern of CEP290 (610142) distribution. Analysis of the SHH (600725) pathway showed that both PTCH1 (601309) and GLI1 (165220) were induced at a lower level in mutant fibroblasts than in controls, and there were increased amounts of full-length unprocessed GLI3 (165240), suggesting that some of the defects seen in these patients might be due to abnormal SHH signaling.
Alby, C., Piquand, K., Huber, C., Megarbane, A., Ichkou, A., Legendre, M., Pelluard, F., Encha-Ravazi, F., Abi-Tayeh, G., Bessieres, B., El Chehadeh-Djebbar, S., Laurent, N., and 18 others. Mutations in KIAA0586 cause lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly syndrome. Am. J. Hum. Genet. 97: 311-318, 2015. Note: Erratum: Am. J. Hum. Genet. 97: 353 only, 2015. [PubMed: 26166481] [Full Text: https://doi.org/10.1016/j.ajhg.2015.06.003]
Bachmann-Gagescu, R., Phelps, I. G., Dempsey, J. C., Sharma, V. A., Ishak, G. E., Boyle, E. A., Wilson, M., Marques Lourenco, C., Arslan, M., University of Washington Center for Mendelian Genomics, Shendure, J., Doherty, D. KIAA0586 is mutated in Joubert syndrome. Hum. Mutat. 36: 831-835, 2015. [PubMed: 26096313] [Full Text: https://doi.org/10.1002/humu.22821]
Davey, M. G., Paton, I. R., Yin, Y., Schmidt, M., Bangs, F. K., Morrice, D. R., Smith, T. G., Buxton, P., Stamataki, D., Tanaka, M., Munsterberg, A. E., Briscoe, J., Tickle, C., Burt, D. W. The chicken talpid-3 gene encodes a novel protein essential for Hedgehog signaling. Genes Dev. 20: 1365-1377, 2006. [PubMed: 16702409] [Full Text: https://doi.org/10.1101/gad.369106]
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]