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KIAA0586
KIAA0586
KIAA0586 is located on the long (q) arm of chromosome 14, at band 14q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
KIAA0586 is located on chromosome 14 at band q23.1 and encodes a 1,533 amino acid protein that plays a critical role in centriole and cilia biology. The protein localises to the centrosome, a cellular structure that organises microtubules and serves as the base from which cilia extend. Cilia are antenna-like organelles that protrude from the cell surface and perform diverse functions, from sensing environmental signals to moving fluid across tissue surfaces.
Disruption of KIAA0586 function impairs the cell's ability to assemble functional cilia, leading to a group of conditions known as ciliopathies. These disorders can manifest with intellectual disability, structural brain malformations including hydrocephalus, eye abnormalities, kidney defects, skeletal dysplasias and facial clefting. The gene is inherited in both autosomal recessive and autosomal dominant patterns, depending on the specific variant and associated condition.
What the gene does
The KIAA0586 protein functions as a structural component required for proper centrosome organisation and ciliogenesis, the process by which cells build cilia. It localises to the centrosome and appears to coordinate the assembly and stabilisation of the ciliary axoneme, the microtubule-based scaffold that forms the cilia core structure. By maintaining centrosomal integrity, KIAA0586 helps ensure that the transition zone between the cell body and the cilium forms correctly, allowing selective transport of proteins into and out of the ciliary compartment.
This gating function is essential because cilia act as signalling hubs that concentrate specific receptors and transduction machinery. Defective KIAA0586 disrupts multiple cilia-dependent pathways, including Hedgehog signalling, which regulates embryonic patterning, and pathways controlling left-right body axis determination. The protein's role extends beyond early development, as cilia continue to function in tissue homeostasis, sensory perception and fluid flow regulation in organs such as the kidney, brain ventricles and respiratory tract.
KIAA0586 interacts with other centrosomal and ciliary proteins to form molecular complexes that anchor and orient the ciliary apparatus. When this coordination fails, cells produce shortened, absent or structurally abnormal cilia that cannot properly transmit signals or perform mechanical functions, leading to the multi-organ phenotypes observed in ciliopathies.
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Chromosome location
KIAA0586 is positioned on the long arm of chromosome 14 at cytogenetic band 14q23.1. This chromosomal region contains multiple genes involved in developmental processes. The genomic structure and precise exon architecture of KIAA0586 contribute to the production of the full-length 1,533 amino acid protein product, though alternative splicing may generate additional isoforms with tissue-specific expression patterns.
Protein structure
The KIAA0586 protein contains several structural features that support its centrosomal and ciliary functions. Two coiled coil domains are present: one spanning amino acids 182-223 and another from residues 467-501. These coiled coil regions typically mediate protein-protein interactions, allowing KIAA0586 to engage with other centrosomal components and assemble into larger molecular scaffolds.
A functionally defined region required for centrosomal localisation extends from amino acids 467-554, overlapping with the second coiled coil domain. This segment is critical for directing the protein to the centrosome, where it can participate in centriole duplication and cilium assembly. Multiple disordered regions are distributed throughout the sequence, including segments at residues 32-57, 309-339, 377-400, 546-575 and 1,129-1,156. Disordered regions often provide flexibility and enable dynamic interactions with binding partners, suggesting that KIAA0586 may function as a platform for assembling regulatory complexes that respond to developmental or environmental cues.
Key variants
Pathogenic variants in KIAA0586 include loss-of-function mutations such as nonsense, frameshift and splice-site changes that reduce or eliminate functional protein production. Missense variants affecting the coiled coil domains or the centrosomal localisation region can disrupt protein interactions or prevent proper subcellular targeting. The spectrum of variants correlates with the severity and range of ciliopathy phenotypes, with complete loss of function generally associated with more severe multi-system involvement.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.12dup | p.Glu5Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 23 |
c.2050C>T | p.Arg684Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome and related disorders |
c.2405del | p.Lys802fs | Pathogenic/Likely pathogenic | ★★☆☆ | Short-rib thoracic dysplasia 14 with polydactyly |
c.2536del | p.Val846fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive KIAA0586-related disorders |
c.2854_2855insG | p.Ile952fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 23 |
c.3097dup | p.Ala1033fs | Pathogenic | ★★☆☆ | Short-rib thoracic dysplasia 14 with polydactyly |
c.3142_3144+5del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Short-rib thoracic dysplasia 14 with polydactyly |
c.3580C>T | p.Gln1194Ter | Pathogenic | ★★☆☆ | Joubert syndrome 23 |
c.3793dup | p.Ile1265fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 23 |
c.38del | p.Lys13fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
KIAA0586-related ciliopathies encompass a range of overlapping developmental disorders characterised by defects in organs that depend on cilia for proper formation or function. Affected individuals may present with structural brain malformations, including abnormal development of the cerebellum and brainstem, as well as hydrocephalus resulting from impaired cerebrospinal fluid circulation. Intellectual disability is common, reflecting disrupted neuronal migration and brain patterning.
Other features can include retinal dystrophy and structural eye anomalies, polycystic kidney disease or renal dysplasia, skeletal abnormalities such as short ribs and polydactyly, and orofacial clefting. The clinical presentation is highly variable, ranging from isolated single-system involvement to severe multi-organ syndromes. This variability likely reflects genetic background, modifier genes and the specific functional impact of individual KIAA0586 variants on cilia assembly and signalling.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic KIAA0586 variants typically follow ar/ad inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
KIAA0586 has been designated with green (high evidence) status on multiple NHS Genomic Medicine Service gene panels, reflecting strong evidence for its role in human disease. It appears on panels for clefting, developmental disorders (DDG2P), foetal anomalies, hydrocephalus, intellectual disability, and various ciliopathy categories including neurological, ophthalmological, renal and skeletal ciliopathies, as well as rare multisystem ciliopathy disorders, structural eye disease and thoracic dystrophies. This broad panel representation underscores the gene's involvement in diverse developmental processes and its clinical relevance for NHS genomic testing pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What are ciliopathies and how does KIAA0586 relate to them?
Ciliopathies are a group of genetic disorders caused by defects in cilia structure or function. KIAA0586 encodes a centrosomal protein essential for building cilia, so pathogenic variants disrupt cilia formation and lead to multi-organ developmental abnormalities characteristic of ciliopathies.
Can KIAA0586 variants cause isolated symptoms or only multi-system disease?
The clinical spectrum is variable. Some individuals with KIAA0586 variants present with isolated features such as intellectual disability or structural brain malformations, while others have severe multi-system involvement affecting the brain, eyes, kidneys and skeleton. Phenotype depends on the specific variant and genetic background.
Is KIAA0586 testing available on the NHS?
Yes, KIAA0586 is included on multiple NHS Genomic Medicine Service gene panels with green (high evidence) designation. Testing may be offered when a patient's clinical features align with ciliopathy phenotypes, developmental disorders, or specific presentations such as hydrocephalus or skeletal dysplasia.