Receptor for Wnt proteins (PubMed:30135577). Most frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes (PubMed:30135577). Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP) (By similarity). In retina, it can be activated by Wnt protein-binding a

Cell membrane

Vitreoretinopathy, exudative 1

An autosomal dominant disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history.

Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis (PubMed:31363885). Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction (By similarity). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:25868050, PubMed:800600

Secreted, extracellular space, extracellular matrix

Microphthalmia, syndromic, 6

A disease characterized by microphthalmia/anophthalmia associated with facial, genital, skeletal, neurologic and endocrine anomalies. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities.

Structural component of hyaline cartilage and vitreous of the eye

Secreted, extracellular space, extracellular matrix

Multiple epiphyseal dysplasia 6

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ13 has a very low single channel conductance, low sensitivity to

MembraneCell membrane

Snowflake vitreoretinal degeneration

Developmental and progressive hereditary eye disorder that affects multiple tissues within the eye. Diagnostic features of SVD include fibrillar degeneration of the vitreous humor, early-onset cataract, minute crystalline deposits in the neurosensory retina, and retinal detachment.

Transcription factor that binds to DNA at the consensus sequence 5'-CAG[GC]TG-3' (PubMed:31696227). Dimerization with TCF3 isoform E47 may be required in certain situations (PubMed:31696227). Binds to gene promoters and enhancer elements, and thereby regulates a transcriptional program of retinal ganglion cell (RGC) determinant genes (By similarity). Although the exact mechanism is not certain, retinal transcription regulation by ATOH7 has a role in RGC determination and survival, photoreceptor

NucleusPerikaryonCell projection, axon

Persistent hyperplastic primary vitreous, autosomal recessive

A developmental eye malformation associated with microphthalmia, cataract, glaucoma, and congenital retinal non-attachment. It is due to failure of the primary vitreous to regress in utero, resulting in the presence of a retrolental fibrovascular membrane with persistence of the posterior portion of the tunica vasculosa lentis and hyaloid artery. Disease manifestations range from a trivial remnant of hyaloid vessels to a dense fibrovascular mass causing lens opacity and retinal detachment.

Mediates phosphorylation of MECP2 (PubMed:15917271, PubMed:16935860). May regulate ciliogenesis (PubMed:29420175)

NucleusCytoplasm, cytoskeleton, cilium basal bodyCytoplasm, cytoskeleton, microtubule organizing center, centrosome

Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA-binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus

NucleusChromosome, telomere

Tumor predisposition syndrome 3

An autosomal dominant disorder characterized by an increased risk for the development of various types of benign and malignant neoplasms throughout life, with age-dependent penetrance. Affected individuals can develop neoplasms involving epithelial, mesenchymal, and neuronal tissues, as well as lymphoid and myeloid cancers. The disorder is associated with elongated telomeres.

May be involved in transcriptional regulation

Nucleus

Vitreoretinopathy, exudative 6

An autosomal dominant form of exudative vitreoretinopathy, a form of exudative vitreoretinopathy, a disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery.

Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation (PubMed:12853446, PubMed:16617111, PubMed:19273597, PubMed:19923322, PubMed:33693784, PubMed:7744004, PubMed:9171063). Acts as a downstream effector of the small GTPases CDC42 and RAC1 (PubMed:7744004). Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequen

CytoplasmNucleusCytoplasm, perinuclear regionMembrane

Knobloch syndrome 2

An autosomal dominant form of Knobloch syndrome characterized by high myopia, vitreoretinal degeneration, retinal detachment, occipital encephalocele or scalp lesions, and mild to severe psychomotor delay.

Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex ha

NucleusChromosome, telomere

Cerebroretinal microangiopathy with calcifications and cysts 2

An autosomal recessive, multisystemic disorder characterized by intrauterine growth retardation and, later in life, premature aging symptoms, including poor growth, graying hair, liver fibrosis, portal hypertension, esophageal varices, osteopenia, pancytopenia, hypocellular bone marrow, and vascular telangiectasia resulting in gastrointestinal bleeding. Brain calcifications and white matter changes are responsible for signs including spasticity, ataxia, or dystonia observed in some patients.

Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:189574

CytoplasmNucleusCytoplasm, cytoskeletonCell junction, adherens junctionCell junctionCell membraneCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasm, cytoskeleton, spindle poleSynapseCytoplasm, cytoskeleton, cilium basal body

Colorectal cancer

A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.

Structural component of hyaline cartilage and vitreous of the eye

Secreted, extracellular space, extracellular matrix

Multiple epiphyseal dysplasia 2

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Plays a role in mitotic spindle assembly and metaphase plate congression (PubMed:27462074)

Cytoplasm, cytoskeleton

Charcot-Marie-Tooth disease, axonal, type 2O

An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy.

Calcium-regulated non-lysosomal thiol-protease

Vitreoretinopathy, neovascular inflammatory

An autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. Patients present during the second or third decade of life with posterior uveitis and reduction of the electroretinogram b-wave. They become more symptomatic when cataracts, cystoid macular edema, and disk edema diminish visual acuity during the second stage. Severe vision loss begins during the third stage when proliferative retinal neovascularization and epiretinal membranes appear. There is an ongoing pigmentary retinal degeneration and peripheral visual field loss during all stages. In the fourth stage, proliferative vitreoretinopathy causes tractional retinal detachments at the macula and vitreous base. The fifth or end-stage disease is marked by phthisis.

Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+) (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Allows the movement of chloride and hydrogencarbonate (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Found in a partiall

Cell membraneBasolateral cell membrane

Macular dystrophy, vitelliform, 2

An autosomal dominant form of macular degeneration that usually begins in childhood or adolescence. VMD2 is characterized by typical 'egg-yolk' macular lesions due to abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. Progression of the disease leads to destruction of the retinal pigment epithelium and vision loss.

Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides (By similarity). May play a role in cell-cell adhesion processes in the retina, via homomeric interaction between octamers present on the surface of two neighboring cells (PubMed:27114531). Required for normal structure and function of the retina (PubMed:19093009)

SecretedCell membrane

Retinoschisis juvenile X-linked 1

A vitreo-retinal dystrophy characterized by macular pathology and by splitting of the superficial layer of the retina. Macular changes are present in almost all cases. In the fundi, radially oriented intraretinal foveomacular cysts are seen in a spoke-wheel configuration, with the absence of foveal reflex in most cases. In addition, approximately half of cases have bilateral peripheral retinoschisis in the inferotemporal part of the retina. Aside from the typical fundus appearance, strabismus, nystagmus, axial hyperopia, defective color vision and foveal ectopy can be present. The most important complications are vitreous hemorrhage, retinal detachment, and neovascular glaucoma.

May play a role in intercellular signaling and in connecting cells with the extracellular matrix. May take part in the regulation of cell motility, growth and differentiation. Binds hyaluronic acid

Secreted, extracellular space, extracellular matrixCell projection, cilium, photoreceptor outer segmentSecreted, extracellular space, extracellular matrix, interphotoreceptor matrixSecreted

Wagner vitreoretinopathy

A rare vitreoretinopathy characterized by an optically empty vitreous cavity with fibrillary condensations and a preretinal avascular membrane. Other optical features include progressive chorioretinal atrophy, perivascular sheating, subcapsular cataract and myopia.

Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces

Secreted, extracellular space, extracellular matrix

Spondyloepiphyseal dysplasia congenital type

Disorder characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems.

Catalyzes the first step in the biosynthesis of chondroitin sulfate, heparan sulfate and dermatan sulfate proteoglycans, such as DCN. Transfers D-xylose from UDP-D-xylose to specific serine residues of the core protein

Golgi apparatus membraneSecreted

Spondyloocular syndrome

A syndrome characterized by cataract, loss of vision due to retinal detachment, facial dysmorphism, facial hypotonia, normal height with disproportional short trunk, osteoporosis, immobile spine with thoracic kyphosis and reduced lumbal lordosis.

Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor. Plays a central role in retinal vascularization by acting as a ligand for FZD4 that signals via stabilizing beta-catenin (CTNNB1) and activating LEF/TCF-mediated transcriptional programs. Acts in concert with TSPAN12 to activate FZD4 independently of the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). May be involved i

Secreted

Norrie disease

Recessive disorder characterized by very early childhood blindness due to degenerative and proliferative changes of the neuroretina. Approximately 50% of patients show some form of progressive mental disorder, often with psychotic features, and about one-third of patients develop sensorineural deafness in the second decade. In addition, some patients have more complex phenotypes, including growth failure and seizure.

Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex ha

NucleusChromosome, telomere

Cerebroretinal microangiopathy with calcifications and cysts 1

An autosomal recessive pleiomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia.

Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube May regulate extracellular matrix-dependent motility and morphogenesis of endothelial and non-endothelial cells; the function requires homotrimerization and implicates MAPK signaling Potently inhibits endothelial cell proliferation and angiogenesis (PubMed:9459295). May inhibit angiogenesis by binding to the heparan sulfate proteoglycans involved in growth factor signaling (By similarity

Secreted, extracellular space, extracellular matrixSecreted, extracellular space, extracellular matrix, basement membraneSecreted

Knobloch syndrome 1

A developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia.

Orphan nuclear receptor of retinal photoreceptor cells. Transcriptional factor that is an activator of rod development and repressor of cone development. Binds the promoter region of a number of rod- and cone-specific genes, including rhodopsin, M- and S-opsin and rod-specific phosphodiesterase beta subunit. Enhances rhodopsin expression. Represses M- and S-cone opsin expression

Nucleus

Enhanced S cone syndrome

Autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. ESCS is also associated with visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration.

May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils

Secreted, extracellular space, extracellular matrix

Stickler syndrome 2

An autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable.

Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins (PubMed:11336703, PubMed:11448771, PubMed:11719191, PubMed:15778503, PubMed:15908424, PubMed:16252235). Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration (PubMed:11336703, PubMed:11719191). In particular, may play an important role in the development of t

MembraneEndoplasmic reticulum

Vitreoretinopathy, exudative 1

An autosomal dominant disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history.

Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:14695475, PubMed:20724660, PubMed:21518757, PubMed:9751060). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:19185524, PubMed:21606507, PubMed:27777308, PubMed

CytoplasmNucleus

Ectodermal dysplasia and immunodeficiency 1

A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. EDAID1 is an X-linked recessive disorder characterized by absence of sweat glands, sparse scalp hair, rare conical teeth and immunological abnormalities resulting in severe infectious diseases. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, and may be fatal in childhood.

Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs. Suprisingly, it only activates the norrin (NDP)-dependent activation of FZD4, while it does not activate the Wnt-dependent activation

Cell membrane

Vitreoretinopathy, exudative 5

An autosomal dominant form of exudative vitreoretinopathy, a disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery.

Structural component of hyaline cartilage and vitreous of the eye

Secreted, extracellular space, extracellular matrix

Multiple epiphyseal dysplasia 3

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.