Component of intercellular desmosome junctions (PubMed:34368962). Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion (PubMed:19717567)

Cell membraneCell junction, desmosomeCytoplasmNucleus

Palmoplantar keratoderma 1, striate, focal, or diffuse

A dermatological disorder characterized by thickening of the skin on the palms and soles, and longitudinal hyperkeratotic lesions on the palms, running the length of each finger.

Plays an adhesive role by integrating collagen bundles. It is probably associated with the surface of interstitial collagen fibrils via COL1. The COL2 domain may then serve as a rigid arm which sticks out from the fibril and protrudes the large N-terminal globular domain into the extracellular space, where it might interact with other matrix molecules or cell surface receptors (By similarity)

Secreted, extracellular space, extracellular matrix

Is an adhesion molecule necessary for normal myelination in the peripheral nervous system. It mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction

Cell membraneMyelin membrane

Charcot-Marie-Tooth disease, demyelinating, type 1B

A dominant demyelinating 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). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet.

Key enzyme in the cholesterol biosynthesis pathway. Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus (PubMed:14766201, PubMed:26200341, PubMed:7639730). Through the production of lanosterol may regulate lens protein aggregation and increase transparency (PubMed:26200341)

Endoplasmic reticulum membrane

Cataract 44

An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function.

Epidermis-specific type I keratin involved in wound healing. Involved in the activation of follicular keratinocytes after wounding, while it does not play a major role in keratinocyte proliferation or migration. Participates in the regulation of epithelial migration by inhibiting the activity of SRC during wound repair

Pachyonychia congenita 3

An autosomal dominant genodermatosis characterized by hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts.

Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:10805775, PubMed:11163209). Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached (PubMed:10805775, PubMed:27380894, PubMed

MembraneCytoplasmGolgi apparatus membrane

IFAP syndrome 1, with or without Bresheck syndrome

An X-linked syndrome characterized by a peculiar triad of follicular ichthyosis, total or subtotal atrichia, and photophobia of varying degree. Histopathologically, the epidermal granular layer is generally well-preserved or thickened at the infundibulum. Hair follicles are poorly developed and tend to be surrounded by an inflammatory infiltrate. A subgroup of patients is described with lamellar rather than follicular ichthyosis. Non-consistent features may include growth and psychomotor retardation, aganglionic megacolon, seizures and nail dystrophy.

Structural component of gap junctions (By similarity). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane (By similarity). Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (By similarity)

Cell membraneCell junction, gap junction

Erythrokeratodermia variabilis et progressiva 2

A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases.

Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:25152456, PubMed:29309642). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure

NucleusMembrane

Deafness, autosomal dominant, 28

A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA28 is characterized by mild to moderate hearing loss across most frequencies that progresses to severe loss in the higher frequencies by the fifth decade.

SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes. SNAREs localized on opposing membranes assemble to form a trans-SNARE complex, an extended, parallel four alpha-helical bundle that drives membrane fusion. SNAP29 is a SNARE involved in autophagy through the direct control of autophagosome membrane fusion with the lysososome membrane. Also plays a role in ciliogenesis by regulating membrane fusions

CytoplasmGolgi apparatus membraneCytoplasmic vesicle, autophagosome membraneCell projection, cilium membrane

Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome

A neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma.

Erythrokeratodermia variabilis et progressiva 5

A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. EKVP5 inheritance is autosomal recessive.

One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell

Cell membraneCell junction, gap junction

Erythrokeratodermia variabilis et progressiva 1

A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases.

One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell

Cell membraneCell junction, gap junction

Ectodermal dysplasia 2, Clouston type

A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD2 is an autosomal dominant condition characterized by atrichosis, nail hypoplasia and deformities, hyperpigmentation of the skin, normal teeth, normal sweat and sebaceous gland function. Palmoplantar hyperkeratosis is a frequent feature. Hearing impairment has been detected in few cases.

Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). Plays a role in normal ectoderm development (PubMed:17847007, PubMed:28589954). Required for normal tooth development (PubMed:17847007, PubMed:28589954, PubMed:29178643). Required for normal postnatal development and maintenance of tongue papillae and sweat ducts (PubMed:28589954). Required for normal proliferation of basal cells in

Secreted, extracellular space, extracellular matrixSecreted

Odonto-onycho-dermal dysplasia

A rare autosomal recessive ectodermal dysplasia characterized by dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin.

Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient (PubMed:18768791, PubMed:8621489). Plays an important role in fluid secretion in salivary glands (By similarity). Required for TRPV4 activation by hypotonicity. Together with TRPV4, controls regulatory volume decrease in salivary epithelial cells (PubMed:16571723). Seems to play a redundant role in water transport in the eye, lung

Apical cell membraneCell membraneCytoplasmic vesicle membrane

Keratoderma, palmoplantar, Bothnian type

A dermatological disorder characterized by diffuse non-epidermolytic hyperkeratosis of the skin of palms and soles. PPKB is frequently complicated by fungal infections.

Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between neighboring cells (By similarity). Forms homotypic and heterotypic channels gated by transjunctional voltage (By similarity). May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph (Probabl

Cell membraneCell junction, gap junctionEndoplasmic reticulumCell junction

Oculodentodigital dysplasia

A disease characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding. Cardiac abnormalities are observed in rare instances.

Involved in transcription regulation by sequestering in the cytoplasm nuclear receptor coactivators such as NCOA1, NCOA2 and NCOA3 (PubMed:17476305). Involved in regulation of caspase-independent apoptosis by sequestering the proapoptotic factor AIFM1 in mitochondria (PubMed:22371500). Pro-apoptotic stimuli can induce its proteasomal degradation allowing the translocation of AIFM1 to the nucleus to induce apoptosis (PubMed:22371500). Involved in the negative control of vitamin D receptor signali

CytoplasmMitochondrion

Palmoplantar keratoderma and woolly hair

A disorder characterized by abnormal thickening of the skin on the palms and soles, in association with woolly scalp hair. Affected individuals manifest a variable degree of striate palmoplantar keratoderma, generally more severe on the soles. Leukonychia is more pronounced on the fingernails than toenails. Scalp hair, body hair, eyebrows, and eyelashes are sparse. The fifth toes show variable degrees of pseudoainhum, ranging from external rotation to a deep sulcus at the digitoplantar fold, accompanied by a bulbous appearance of the distal toe.

Transaminase involved in tyrosine breakdown. Converts tyrosine to p-hydroxyphenylpyruvate. Can catalyze the reverse reaction, using glutamic acid, with 2-oxoglutarate as cosubstrate (in vitro). Has much lower affinity and transaminase activity towards phenylalanine

Tyrosinemia 2

An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, and oculocutaneous manifestations. Typical features include palmoplantar keratosis, painful corneal ulcers, and intellectual disability.

Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation. Does not exhibit any protease activity on its own

Endoplasmic reticulum membraneCell membrane

Tylosis with esophageal cancer

An autosomal dominant syndrome characterized by focal non-epidermolytic palmoplantar keratoderma, oral leukokeratosis, and a high lifetime risk of developing esophageal squamous cell carcinoma.

Palmoplantar keratoderma, non-epidermolytic, focal or diffuse

A dermatological disorder characterized by non-epidermolytic abnormal thickening of the skin on the palms and soles. Diffuse palmoplantar keratoderma is characterized by uniform involvement of the palmoplantar surface, while the focal form consists of localized areas of hyperkeratosis located mainly on pressure points and sites of recurrent friction.

Has an antitumor activity (PubMed:8742060). Was found to be a marker of late differentiation of the skin. Implicated in maintaining the physiological and structural integrity of the keratinocyte layers of the skin (PubMed:14721776, PubMed:17008884). In vitro down-regulates keratinocyte proliferation; the function may involve the proposed role as modulator of nicotinic acetylcholine receptors (nAChRs) activity. In vitro inhibits alpha-7-dependent nAChR currents in an allosteric manner (PubMed:145

Secreted

Mal de Meleda

A rare autosomal recessive skin disorder, characterized by diffuse transgressive palmoplantar keratoderma with keratotic lesions extending onto the dorsa of the hands and the feet (transgrediens). Patients may have hyperhidrosis. Other features include perioral erythema, lichenoid plaques on the knees and the elbows, and nail abnormalities.

A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:25733715). Critical for cell-cell adhesion in early stage blastocysts and progression through proamniotic cavity formation (By similarity). Not required for preimplantation morphogenic process in blastocysts (By similarity). Required for keratin filament anchoring at the desmosome junction and subsequent organization of the keratin intermediate filament network within the cytoplas

Cell projection, axonCell junction, desmosomeCell membraneCytoplasmNucleus

Keratoderma, palmoplantar, striate 2

A dermatological disorder characterized by thickening of the skin on the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present.

Thiol protease (PubMed:1586157). Has dipeptidylpeptidase activity (PubMed:1586157). Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids (PubMed:1586157). Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate (PubMed:1586157). Can act as both an exopeptidase and endopeptidase (PubMed:1586157). Activates serine proteases such as elastase, cathepsin G and granzymes A and B (PubMed:8428921)

Lysosome

Papillon-Lefevre syndrome

An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees.

Calcium-activated selective cation channel that mediates membrane depolarization (PubMed:12015988, PubMed:12842017, PubMed:29211723, PubMed:30528822). While it is activated by increase in intracellular Ca(2+), it is impermeable to it (PubMed:12015988). Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane (PubMed:12015988). It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, e

Cell membraneEndoplasmic reticulumGolgi apparatus

Progressive familial heart block 1B

A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His-Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death.

Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors (PubMed:29769720). Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an import

SecretedNucleus

Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal

A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin.

Non-selective calcium permeant cation channel (PubMed:12077604, PubMed:12077606, PubMed:26818531, PubMed:37648856, PubMed:38691614). It is activated by innocuous (warm) temperatures and shows an increased response at noxious temperatures greater than 39 degrees Celsius (PubMed:12077604, PubMed:12077606). Activation exhibits an outward rectification (PubMed:12077604). The channel pore can dilate to provide permeability to larger cations (PubMed:37648856). May associate with TRPV1 and may modulate

Cell membraneCytoplasmLysosome

Olmsted syndrome 1

An autosomal dominant, rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at all lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas. The digital constriction may progress to autoamputation of fingers and toes.

May be involved in endocytic recycling of growth factor receptors such as EGFR

Cytoplasm, cytosol

Keratoderma, palmoplantar, punctate 1A

An autosomal dominant dermatological disorder characterized by multiple hyperkeratotic, centrally indented, papules that develop in early adolescence, or later, and are irregularly distributed on the palms and soles (other palmoplantar keratoses have mostly diffuse hyperkeratinization). In mechanically irritated areas, confluent plaques can be found. Interfamilial and intrafamilial severity shows broad variation. In some cases, PPKP1 is associated with the development of early- and late-onset malignancies, including squamous cell carcinoma.

Protein that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization (PubMed:22960744, PubMed:21820097). Combines the ATP-dependent ability to exchange histones, with the chaperone-like ATP-independent activity to deposit histones and assemble nucleosomes (PubMed:21820097). Promotes DNA end resection of double-strand breaks (DSBs) following DNA damage: probably acts by weakening histone DNA interactions in nucleosomes

NucleusChromosome

Adermatoglyphia

An autosomal dominant condition characterized by the lack of epidermal ridges on the palms and soles, which results in the absence of fingerprints, and is associated with a reduced number of sweat gland openings and reduced sweating of palms and soles.

Pachyonychia congenita 4

An autosomal dominant genodermatosis characterized by hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts.

Major keratinocyte cell envelope protein

CytoplasmNucleus, nucleoplasm

Vohwinkel syndrome with ichthyosis

A variant form of Vohwinkel syndrome without hearing loss and associated with ichthyosiform dermatosis. Clinical features include palmoplantar keratoderma, pseudoainhum and ichthyosis. Compact hyperkeratosis with round retained nuclei and hypergranulosis is observed on skin biopsies.

Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair (By similarity). Required for the correct growth of hair follicles, in particular for the persistence of the anagen (growth) state (By similarity). Modulates the function of TNF in the specific context of hair cycling. Regulates protein synthesis and epithelial cell growth through binding to the adapter protein SFN and by stimulating Akt/mTOR pathway (By

Cytoplasm

Pachyonychia congenita 2

An autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy resulting in onchyogryposis (thickening and increase in curvature of the nail), palmoplantar keratoderma and hyperhidrosis, follicular hyperkeratosis, multiple epidermal cysts, absent/sparse eyebrow and body hair, and by the presence of natal teeth.

The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro

CytoplasmNucleus

Epidermolysis bullosa simplex 1A, generalized severe

A form of epidermolysis bullosa simplex, a group of skin fragility disorders characterized by skin blistering due to cleavage within the basal layer of keratinocytes, and erosions caused by minor mechanical trauma. There is a broad spectrum of clinical severity ranging from minor blistering on the feet, to subtypes with extracutaneous involvement and a lethal outcome. EBS1A is an autosomal dominant form characterized by generalized intraepidermal skin blistering that begins and is very prominent at birth. EBS1A may be life-threatening in the first year of life. Tendency to blistering diminishes in adolescence.

Catalyzes the reduction of 3'-oxosphinganine (3-ketodihydrosphingosine/KDS) to sphinganine (dihydrosphingosine/DHS), the second step of de novo sphingolipid biosynthesis

Endoplasmic reticulum membrane

Required for normal Golgi function

Golgi apparatus membrane

Congenital disorder of glycosylation 2L

A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. Clinical features of CDG2L include neonatal intractable focal seizures, vomiting, loss of consciousness, intracranial bleeding due to vitamin K deficiency, and death in infancy.

May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly

Palmoplantar keratoderma, epidermolytic, 1

A form of epidermolytic palmoplantar keratoderma, a dermatological disorder characterized by diffuse thickening of the epidermis on the entire surface of palms and soles sharply bordered with erythematous margins. Some patients may present knuckle pads, thick pads of skin appearing over the proximal phalangeal joints. EPPK1 inheritance is autosomal dominant.

Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:12191486, PubMed:17349957, PubMed:22665479, PubMed:27662089, PubMed:31484767, PubMed:33093214, PubMed:33410748, PubMed:33731929, PubMed:33731932, PubMed:35857590). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critic

Cytoplasm, cytosolCytoplasmNucleusInflammasome

Vitiligo-associated multiple autoimmune disease 1

A disorder characterized by the association of vitiligo with several autoimmune and autoinflammatory diseases including autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus.

Structural component of gap junctions (PubMed:16849369, PubMed:17551008, PubMed:19340074, PubMed:19384972, PubMed:21094651, PubMed:26753910). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane (PubMed:17551008, PubMed:19340074, PubMed:21094651, PubMed:26753910). Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:16849369, PubM

Cell membraneCell junction, gap junction

Deafness, autosomal recessive, 1A

A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.

Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes (PubMed:31630791). The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules

Golgi apparatusCytoplasmic vesicle, clathrin-coated vesicle membrane

Keratitis-ichthyosis-deafness syndrome, autosomal recessive

An autosomal recessive form of keratitis-ichthyosis-deafness syndrome, a disease characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. KIDAR patients manifest ichthyosis, failure to thrive and developmental delay in childhood, thrombocytopenia, photophobia, and progressive hearing loss. Low plasma copper and ceruloplasmin levels have been reported in some patients.

May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1). In complex with C1QBP is a high affinity receptor for kininogen-1/HMWK

Cell membraneCytoplasm

Epidermolytic hyperkeratosis 1

A skin disorder characterized by widespread blistering and an ichthyotic erythroderma at birth that persist into adulthood. Histologically there is a diffuse epidermolytic degeneration in the lower spinous layer of the epidermis. Within a few weeks from birth, erythroderma and blister formation diminish and hyperkeratoses develop. EHK1 inheritance is autosomal dominant or autosomal recessive.

Might function as an inhibitor of Lys-specific proteases. Might influence the maturation of megakaryocytes via its action as a serpin

Cytoplasm

Keratoderma, palmoplantar, Nagashima type

An autosomal recessive, non-syndromic, diffuse palmoplantar keratosis characterized by well-demarcated diffuse erythematous hyperkeratosis expanding onto the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis is mild and non-progressive.

Epidermis-specific type I keratin that plays a key role in skin. Acts as a regulator of innate immunity in response to skin barrier breach: required for some inflammatory checkpoint for the skin barrier maintenance

Pachyonychia congenita 1

An autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy resulting in onchyogryposis (thickening and increase in curvature of the nail), palmoplantar keratoderma, follicular hyperkeratosis, and oral leukokeratosis. Hyperhidrosis of the hands and feet is usually present.

Component of intercellular desmosome junctions (By similarity). Plays a role in stratified epithelial integrity and cell-cell adhesion by promoting desmosome assembly (By similarity). Thereby plays a role in barrier function of the skin against infection (By similarity). Plays a role in mammary epithelial tissue homeostasis and remodeling during and after pregnancy, potentially via its involvement in desmosome cell-cell junctions (By similarity). Required for tooth enamel development via facilit

Cell junction, desmosomeCell membraneCytoplasm

Erythrokeratodermia variabilis et progressiva 7

A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. EKVP7 is an autosomal recessive form characterized by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet, as well as erythematous annular skin lesions. Pruritus, woolly hair, and dystrophic nails may also be present.