NucleusNucleus, nucleolus

Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity)

Cell projection, cilium membrane

Joubert syndrome 20

A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease.

Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms (PubMed:21633164). Involved in the regulation of microtubular dynamics. Required for proper organization of the ciliary tip and control of ciliary localization of SUFU-GLI2 complexes (By similarity). Required for localization of GLI3 to cilia in response to Shh. Neg

Cell projection, ciliumCytoplasm, cytoskeleton, cilium basal body

Promotes the release of prenylated target proteins from cellular membranes (PubMed:9712853). Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location (PubMed:22002721, PubMed:23698361). Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E (PubMed:24166846). Required for RAB28 localization to the cone cell outer segments in the retina (By similarity). Modulates the subcellular location of target proteins by

Cytoplasm, cytosolCytoplasmic vesicle membraneCytoplasm, cytoskeleton, cilium basal body

Joubert syndrome 22

A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly.

Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase. Probable tumor suppressor involved in cell growth, cell proliferation and apoptosis that regulates p53/TP53 stability through ubiquitin-dependent degradation. May regulate chromatin modification through sumoylation of several chromatin modification-associated proteins. May be involved in DNA damage-induced cell death through IKBKE sumoylation

NucleusNucleus, PML body

Retinitis pigmentosa 31

A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.

Involved in the localization of proteins to the cilium and cilium assembly. Indirectly regulates the signaling functions of the cilium, being required for normal SHH/smoothened signaling and proper development

Cell projection, cilium

Joubert syndrome 36

A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS36 inheritance is autosomal recessive.

Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164 (By similarity). Involved in the biogenesis of the cilium, a centriole-associated function. The cilium is a cell surface projection found in many vertebrate cells required to transduce signals important for development and tissue homeostasis (PubMed:33934390). Plays an important role in development by regulating Wnt signa

Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centrioleCytoplasm, cytoskeleton, cilium basal bodyNucleusCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite

Orofaciodigital syndrome 1

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD1 is X-linked dominant syndrome, lethal in males. Craniofacial findings consist of facial asymmetry, hypertelorism, median cleft, or pseudocleft of the upper lip, hypoplasia of the alae nasi, oral clefts and abnormal frenulea, tongue anomalies (clefting, cysts, hamartoma), and anomalous dentition involving missing or extra teeth. Asymmetric brachydactyly and/or syndactyly of the fingers and toes occur frequently. Approximately 50% of OFD1 females have some degree of intellectual disability. Some patients have structural central nervous system anomalies such as agenesis of the corpus callosum, cerebellar agenesis, or a Dandy-Walker malformation. Patients with OFD1 can develop fibrocystic disease of the liver and pancreas, in addition to polycystic kidneys.

Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling pathway. Disrupts the interaction of GLI2 and GLI3 with the negative regulator SUFU. Inhibiting SUFU's interaction with GLI2 promotes the entry of GLI2 into the nucleus, allowing it to activate Hh target gene expression. Disrupting SUFU's interaction with GLI3 prevents its conversion into the repressor form, leading to increased nuclear GLI3 and enhanced Hh signaling. Required for

MembraneCytoplasm, cytoskeleton, cilium basal body

Joubert syndrome 2

A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease.

Required for the formation of cilia. Plays an indirect role in sonic hedgehog signaling, cilia being required for all activity of the hedgehog pathway (By similarity). Together with RAB23 and KIF17, it is required for the localization of specific G protein-coupled receptors, such as dopamime receptor DRD1, to primary cilia (PubMed:26182404). Has pro-apoptotic function via its interaction with HIP1, leading to recruit caspase-8 (CASP8) and trigger apoptosis. Has the ability to bind DNA sequence m

Cell projection, ciliumCytoplasm, cytoskeleton, cilium basal body

Orofaciodigital syndrome 18

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD18 is an autosomal recessive form characterized by short stature, brachymesophalangy, pre- and postaxial polysyndactyly, and stocky femoral necks, as well as oral anomalies and dysmorphic facial features.

Involved in centriole duplication (PubMed:24613305, PubMed:26297806). Positively regulates CEP63 centrosomal localization (PubMed:24613305, PubMed:26297806). Required for WDR62 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:24613305, PubMed:26297806). May play a role in cilium assembly

Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centrioleCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satelliteCytoplasm, cytoskeleton, microtubule organizing center, centrosome

Orofaciodigital syndrome 15

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD15 features include facial dysmorphism, lobulated tongue, clefting of the alveolar ridges, left hand postaxial polydactyly, broad right hallux and left hallux duplication, and intermittent respiratory difficulty. Brain anomalies include vermis hypoplasia with molar tooth sign, agenesis of corpus callosum, and ventricular dilation. OFD15 inheritance is autosomal recessive.

Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity (PubMed:20230784). Involved in DNA damage checkpoint control and for proper DNA damage repair (PubMed:20230784). In response to injury that includes DNA damage, NEK1 phosphorylates VDAC1 to limit mitochondrial cell death (PubMed:20230784). May be implicated in the control of meiosis (By similarity). Involved in cilium assembly (PubMed:21211617)

NucleusCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasm

Short-rib thoracic dysplasia 6 with or without polydactyly

A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome.

Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling (By similarity). Proposed to fun

CytoplasmCell surfaceCytoplasm, cytoskeleton, cilium basal bodyCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole

Short-rib thoracic dysplasia 20 with polydactyly

A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome.

Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). May be involved in apoptosis regulation. Necessary for signal transduction through the sonic hedgehog (Shh) signaling pathway

Membrane

Orofaciodigital syndrome 4

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD4 patients have tongue nodules, multiple frenulae, broad flat nose, hypertelorism, and short rib polydactyly with tibial dysplasia (Majewski syndrome). The presence of severe tibial aplasia differentiates OFD4 from OFD1. Additional features of cystic dysplastic kidneys and brain malformation, including occipital encephalocele, are observed in severely affected patients.

Pre-mRNA-binding protein required for splicing of both U2- and U12-type introns. Selectively interacts with the 3'-splice site of U2- and U12-type pre-mRNAs and promotes different steps in U2 and U12 intron splicing. Recruited to U12 pre-mRNAs in an ATP-dependent manner and is required for assembly of the pre-spliceosome, a precursor to other spliceosomal complexes. For U2-type introns, it is selectively and specifically required for the second step of splicing

Nucleus

Orofaciodigital syndrome 21

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD21 is an X-linked recessive form characterized by postaxial polydactyly of the hands, hallux duplication, palatal defects, fused incisors, accessory oral frenula and tongue nodules, in association with brain anomalies that range from pituitary anomalies to alobar holoprosencephaly.

Plays a role in cilia formation and embryonic patterning. Requires for normal Sonic hedgehog (Shh) signaling in the neural tube and acts in combination with GLI2 and GLI3 to pattern ventral and intermediate neuronal cell types (By similarity). During ciliogenesis regulates the ciliary transition zone localization of some MKS complex proteins (PubMed:26518474)

MembraneCell projection, cilium

Meckel syndrome 13

A form of Meckel syndrome, a disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly.

As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:36084634). Plays a role in the regulation of primary cilia length and Hedgehog signaling (PubMed:36084634)

Nucleus, nucleoplasmNucleus speckle

Orofaciodigital syndrome 19

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD19 is an autosomal recessive form characterized by tongue nodules, dental and digital anomalies, narrow high-arched or cleft palate, and retrognathia. Some patients have notching of the upper or lower lip.

Required for high-level Shh responses in the developing neural tube. Together with CDK20, controls the structure of the primary cilium by coordinating assembly of the ciliary membrane and axoneme, allowing GLI2 to be properly activated in response to Shh signaling (By similarity)

CytoplasmCell projection, cilium

Orofaciodigital syndrome 9

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD9 is an autosomal recessive form characterized by a variable phenotype. Clinical features are midline defects, including abnormal pituitary development that results in variable pituitary hormone deficiencies, facial dysmorphic features including frontal bossing and hypertelorism, and variable eye defects including microphthalmia, coloboma, and retinal dystrophy. Affected individuals manifest variable psychomotor development.

Component of the centrioles that acts as a positive regulator of centriole elongation (PubMed:24997988). Promotes assembly of centriolar distal appendage, a structure at the distal end of the mother centriole that acts as an anchor of the cilium, and is required for recruitment of centriolar distal appendages proteins CEP83, SCLT1, CEP89, FBF1 and CEP164. Not required for centriolar satellite integrity or RAB8 activation. Required for primary cilium formation (PubMed:23769972). Required for soni

Cytoplasm, cytoskeleton, cilium basal bodyCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole

Orofaciodigital syndrome 14

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD14 patients show severe microcephaly, cerebral malformations the molar tooth sign, and intellectual disability in addition to canonical OFDS features.

Involved in ciliogenesis (PubMed:25877302, PubMed:35582950). Involved in the establishment of cell polarity required for directional cell migration. Proposed to act in association with the CPLANE (ciliogenesis and planar polarity effectors) complex. Involved in recruitment of peripheral IFT-A proteins to basal bodies (By similarity)

MembraneCell projection, cilium

Joubert syndrome 17

A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease.

CytoplasmNucleus

Orofaciodigital syndrome 5

A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD5 patients show the core features of cleft palate, lobulated tongue, and polydactyly. Additional features include frontal bossing and intellectual disability.