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Inheritance

2

Autosomal dominant HP:0000006

EKV is most often inherited in an autosomal dominant pattern, with marked intra- and interfamilial variability and documented incomplete penetrance.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

PMID:34717022 SUPPORT Human Clinical

"The majority of EKVP cases display an autosomal dominant mode of inheritance with incomplete penetrance, although recessive transmission has also been described."

Directly supports autosomal dominant inheritance as the major transmission pattern and explicitly notes incomplete penetrance.

PMID:9843209 SUPPORT Human Clinical

"Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability."

Foundational family-based evidence supporting dominant inheritance with variable expression.

Autosomal recessive HP:0000007

Recessive EKV is uncommon but established, particularly in consanguineous pedigrees with biallelic GJB3 variants.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:21564177 SUPPORT Human Clinical

"Autosomal recessive inheritance should be considered when providing genetic counselling to consanguineous families at risk for EKV."

Directly supports recessive transmission in EKV.

PMID:22266302 SUPPORT Human Clinical

"EKV is mainly inherited as an autosomal dominant disease, although recessive transmission has occasionally been reported."

Confirms that recessive inheritance is part of the EKV disease spectrum even though it is less common.

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Subtypes

7

EKVP1 (GJB3 / connexin 31) MONDO:0033010

GJB3 hgnc:4285

Connexin-31 form. Heterozygous GJB3 missense mutations were identified in four EKV families, and a recessive GJB3 allele has since been reported in a consanguineous pedigree, so this subtype spans both transmission modes.

Show evidence (1 reference)

PMID:9843209 SUPPORT Human Clinical

"We detected heterozygous missense mutations in GJB3 in four EKV families"

Establishes GJB3 as the gene of the first numbered EKVP subtype in four independent families.

EKVP2 (GJB4 / connexin 30.3) MONDO:0033012

GJB4 hgnc:4286

Connexin-30.3 form, found by sequencing GJB4 in EKV families without a detectable GJB3 mutation. Two GJB4 mutations were associated with rapidly changing erythematous patches with prominent, circinate or gyrate borders in affected children but not in adults.

Show evidence (2 references)

PMID:12648223 SUPPORT Human Clinical

"Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls."

Establishes GJB4 as a second connexin gene of the EKVP series in families screened because they carried no GJB3 mutation.

PMID:12648223 SUPPORT Human Clinical

"Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects."

Source for the circinate-border feature stated in this subtype's description, including that it was seen in children and not adults.

EKVP3 (GJA1 / connexin 43) MONDO:0033013

GJA1 hgnc:4274

Connexin-43 form, caused by de novo dominant GJA1 missense mutations. The skin disease is reported as distinct from the limited cutaneous findings rarely seen in oculodentodigital dysplasia, which dominant GJA1 mutations also cause.

Show evidence (1 reference)

PMID:25398053 SUPPORT Human Clinical

"By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP."

Establishes GJA1 as the third connexin gene of the EKVP series.

EKVP4 (KDSR-related, recessive) MONDO:0033014

KDSR hgnc:4021

Recessive ceramide-synthesis form caused by biallelic KDSR mutations. The reported phenotype sits in the progressive symmetric erythrokeratoderma spectrum rather than the migratory-patch picture of the connexin subtypes: severe lesions of thick scaly skin on the face and genitals, and thickened, red and scaly skin on the hands and feet. Systemic isotretinoin achieved nearly complete resolution in the two probands in whom it was applied.

Show evidence (3 references)

PMID:28575652 SUPPORT Human Clinical

"we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum"

Establishes biallelic KDSR mutation as a recessive cause in the erythrokeratoderma spectrum, and names the affected enzymatic step.

PMID:28575652 SUPPORT Human Clinical

"This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet."

Source for the lesion distribution given in this subtype's description.

PMID:28575652 SUPPORT Human Clinical

"Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation."

Source for the isotretinoin response noted in this subtype's description, including how many probands were treated.

EKVP5 (KRT83-related, recessive) MONDO:0033015

KRT83 hgnc:6460

Recessive form attributed to a homozygous KRT83 frameshift deletion in one large Pakistani kindred, presenting as progressive symmetric erythrokeratoderma. KRT83 is a hair keratin, and heterozygous KRT83 missense substitutions cause dominant monilethrix, so the two diseases are reported as allelic.

Show evidence (2 references)

PMID:27965375 SUPPORT Human Clinical

"Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."

The single reported kindred establishing KRT83 as a recessive erythrokeratoderma gene, and the basis for calling the allele a predicted null rather than a demonstrated one.

PMID:27965375 SUPPORT Human Clinical

"Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene."

Source for the allelism with monilethrix stated in this subtype's description.

EKVP6 (TRPM4-related, dominant) MONDO:0032801

TRPM4 hgnc:17993

Dominant channelopathy form. Two missense mutations in the S6 transmembrane domain of TRPM4, found in three separate families with progressive symmetric erythrokeratodermia, make the channel hyperactive rather than abolishing it, so this is the one EKVP subtype whose reported mechanism is a gain of function.

Show evidence (1 reference)

PMID:30528822 SUPPORT Human Clinical

"In three separate families with progressive symmetric erythrokeratodermia, we identified two missense mutations (c.3099C>G and c.3119T>C) that produce p.Ile1033Met and p.Ile1040Thr, both of which are located in the S6 transmembrane domain of the TRPM4 protein."

Establishes TRPM4 as an EKVP-series gene, gives the number of families, and locates both alleles in the S6 domain as this description states.

EKVP7 (PERP-related, recessive) MONDO:0030941

PERP hgnc:17637

Recessive desmosomal form. Homozygosity for an N-terminal PERP truncation ablates expression and causes widespread erythrokeratoderma. The same gene causes Olmsted syndrome when a C-terminal truncation is heterozygous, and the reporting authors propose that the two PERP diseases have distinct pathobiology rather than differing only in severity.

Show evidence (2 references)

PMID:30321533 SUPPORT Human Clinical

"Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers."

Establishes biallelic PERP loss of expression as a cause of widespread erythrokeratoderma, which is the EKVP7 phenotype.

PMID:30321533 SUPPORT Human Clinical

"Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."

Source for the statement that a different PERP allele class causes Olmsted syndrome, which is why EKVP7 is not the only PERP disease.

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Pathophysiology

8

Connexin Mislocalization

Pathogenic EKV variants disrupt connexin trafficking or membrane localization, preventing normal delivery of epidermal connexins to the cell surface. Mislocalization has been shown for all three connexin genes of the EKVP series - Cx31 (GJB3), Cx30.3 (GJB4) and Cx43 (GJA1) - so this node is the shared entry point of the connexin subtypes EKVP1 to EKVP3.

keratinocyte CL:0000312

GJB3 hgnc:4285 GJB4 hgnc:4286 GJA1 hgnc:4274

protein localization to plasma membrane GO:0072659 ⚠ ABNORMAL

gap junction channel activity GO:0005243 ↓ DECREASED

skin epidermis UBERON:0001003

Downstream

Impaired Gap Junction Assembly Loss of membrane-targeted connexins reduces the capacity of keratinocytes to form effective epidermal gap junctions.

Show evidence (3 references)

PMID:21564177 SUPPORT In Vitro

"Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation."

Directly shows that a recessive GJB3 EKV mutation disrupts membrane targeting.

PMID:30924322 SUPPORT Human Clinical

"GJA1 P283L and T290N mutations lead to Cx43 protein cytoplasmic mislocalization."

Supports connexin mislocalization as a recurrent mechanism in GJA1-related EKV.

PMID:34717022 SUPPORT In Vitro

"while wild-type GJB4 localized at the cell membrane of HeLa cells forming intercellular junctions and intracellular puncta, V37M mutant variant was diffusely expressed within HeLa cells at a considerably lower level"

Extends the mislocalization mechanism to the third connexin gene bound on this node, GJB4, which the other two evidence items do not cover.

Impaired Gap Junction Assembly

Loss of membrane-targeted connexins reduces keratinocyte participation in epidermal gap-junction networks and disrupts intercellular signaling across the epidermis.

keratinocyte CL:0000312

gap junction assembly GO:0016264 ⚠ ABNORMAL cell-cell signaling GO:0007267 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Abnormal Epidermal Homeostasis and Keratinization Loss of effective epidermal gap-junction communication disrupts the differentiation programs that normally maintain cutaneous homeostasis.

Show evidence (1 reference)

PMID:21564177 SUPPORT In Vitro

"Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation."

Directly supports impaired gap-junction formation downstream of connexin mislocalization.

Abnormal Epidermal Homeostasis and Keratinization

Impaired epidermal differentiation and homeostasis, producing persistent hyperkeratosis and episodic erythematous lesions. This is the convergence point of every subtype in the entry: the connexin subtypes reach it through failed gap-junction communication, and the non-connexin subtypes reach it through deficient ceramide synthesis, desmosome immaturity, keratinocyte hyperproliferation, or loss of keratin 83.

keratinocyte CL:0000312

keratinization GO:0031424 ⚠ ABNORMAL cell-cell signaling GO:0007267 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Transient figurate erythematous patches Disturbed epidermal homeostasis produces episodic figurate erythematous patches.

Fixed hyperkeratotic plaques Abnormal keratinization produces persistent hyperkeratotic plaques.

Palmoplantar keratoderma Palmoplantar epidermal keratinization defects manifest as palmoplantar keratoderma.

Show evidence (2 references)

PMID:9843209 SUPPORT Human Clinical

"Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors."

Supports disturbed epidermal differentiation as a core mechanistic consequence of GJB3-mediated EKV.

PMID:25398053 SUPPORT Human Clinical

"These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1."

Supports abnormal epidermal homeostasis as a mechanistic endpoint in the GJA1-related branch of EKV.

Epidermal Ceramide Synthesis Deficiency

The EKVP4 route. KDSR catalyses a step of the ceramide synthesis pathway, and the reported biallelic EKVP4 alleles were shown by immunohistochemistry and yeast complementation to impair KDSR function. Ceramide output is therefore reduced rather than merely altered - an inference the isotretinoin response supports, since the authors read it as recruitment of alternative pathways for ceramide generation.

keratinocyte CL:0000312

KDSR hgnc:4021

ceramide biosynthetic process GO:0046513 ↓ DECREASED

3-dehydrosphinganine reductase activity GO:0047560 ↓ DECREASED

skin epidermis UBERON:0001003

Downstream

Abnormal Epidermal Homeostasis and Keratinization Deficient epidermal ceramide synthesis produces the scaly hyperkeratotic phenotype. The steps between the enzymatic defect and the epidermal lesion are not characterized in the reporting study.

Show evidence (2 references)

PMID:28575652 SUPPORT In Vitro

"Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function."

Functional demonstration that the EKVP4 alleles impair the enzyme, which is what this node asserts.

PMID:28575652 SUPPORT Human Clinical

"Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation."

Cited for the directional reading of the node: the authors attribute the retinoid response to alternative ceramide generation, which presupposes that ceramide output is deficient.

TRPM4 Cation Channel Hyperactivity

The EKVP6 route, and the only gain-of-function mechanism in the entry. Both reported alleles sit in the S6 transmembrane domain, where the cryo-EM structures predict a direct effect on activation gating, and electrophysiology of the mutants shows raised baseline activity, greater sensitivity to intracellular Ca2+ and a higher resting membrane potential.

keratinocyte CL:0000312

TRPM4 hgnc:17993

calcium-activated cation channel activity GO:0005227 ⇑ GAIN OF FUNCTION

skin epidermis UBERON:0001003

Downstream

Keratinocyte Hyperproliferation Keratinocytes overexpressing either mutant channel proliferate more than controls, so channel hyperactivity drives the proliferative state.

Show evidence (2 references)

PMID:30528822 SUPPORT In Vitro

"Electrophysiological studies of the mutants showed substantial hyperactivity, as evidenced by pronounced baseline activity, enhanced sensitivity to intracellular Ca2+, and an elevated resting membrane potential."

The measurement behind this node: the mutant channels are hyperactive, not merely mislocalized or lost.

PMID:30528822 SUPPORT Computational

"The substitutions are expected to directly affect activation gating of TRPM4 according to the cryo-EM structures."

Structural basis for placing the lesion at the activation gate, which the node's description states as a prediction rather than a measurement.

Desmosome Maturation Failure

The EKVP7 route. Skin from a subject homozygous for the N-terminal PERP truncation shows desmosomes lacking the electron-dense midline of mature desmosomes, with reduced desmosome numbers and increased fragmentation after mechanical stress, while other desmosomal components localize normally. The exact function of PERP within the desmosome is not known.

keratinocyte CL:0000312

PERP hgnc:17637

desmosome organization GO:0002934 ⚠ ABNORMAL

structural molecule activity GO:0005198 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Abnormal Epidermal Homeostasis and Keratinization Immature desmosomes and impaired adhesion accompany the widespread erythrokeratoderma of EKVP7. The reporting authors state that the exact function of PERP in desmosomes is unknown, so the intervening steps are not established.

Show evidence (2 references)

PMID:30321533 SUPPORT Human Clinical

"Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress."

The electron-microscopy and dissociation findings in subject skin that this node asserts.

PMID:30321533 SUPPORT Human Clinical

"Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins."

Source for restricting the node's claim to desmosome maturation rather than to loss of the desmosomal protein complement.

Keratinocyte Hyperproliferation

Increased keratinocyte proliferation, reported for both non-connexin dominant and recessive routes in this entry: keratinocytes overexpressing either mutant TRPM4 channel show enhanced proliferation, and skin from both the dominant and recessive PERP subjects is hyperproliferative. Only TRPM4 carries a downstream edge into this node. The PERP route reaches it through the gene binding alone, because the PERP report establishes that the skin is hyperproliferative without establishing whether that follows the desmosome maturation failure or accompanies it.

keratinocyte CL:0000312

TRPM4 hgnc:17993 PERP hgnc:17637

keratinocyte proliferation GO:0043616 ↑ INCREASED

skin epidermis UBERON:0001003

Downstream

Abnormal Epidermal Homeostasis and Keratinization Increased keratinocyte proliferation accompanies the up-regulation of proliferation and differentiation markers seen in affected skin, and contributes to the hyperkeratotic phenotype.

Show evidence (2 references)

PMID:30528822 SUPPORT In Vitro

"In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants."

The TRPM4 arm of this node's claim, measured in cultured keratinocytes.

PMID:30321533 SUPPORT Human Clinical

"Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress."

The PERP arm of this node's claim, observed in subject skin.

Keratin 83 Loss of Function

The EKVP5 route, and the least characterized. The single reported kindred carries a homozygous KRT83 frameshift that the authors state is expected to abolish keratin 83, a type II keratin of hair and skin. That expectation is the whole of the molecular claim available, so this node records a predicted null and asserts nothing about how it reaches the epidermis.

KRT83 hgnc:6460

structural constituent of cytoskeleton GO:0005200 ⇓ LOSS OF FUNCTION

skin epidermis UBERON:0001003

Downstream

Abnormal Epidermal Homeostasis and Keratinization Loss of keratin 83 co-segregates with the progressive symmetric erythrokeratoderma phenotype. The authors' own conclusion is hedged to "at least some cases", and no intervening epidermal mechanism is reported.

Show evidence (1 reference)

PMID:27965375 SUPPORT Human Clinical

"Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."

The whole basis of this node: a co-segregating frameshift whose protein effect is stated as an expectation.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

3

Cardiovascular 1

Transient figurate erythematous patches Migratory erythematous plaque HP:0033622

Show evidence (2 references)

PMID:26945536 SUPPORT Human Clinical

"Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches."

Directly supports transient erythematous lesions as a core phenotype of EKV.

PMID:16854764 SUPPORT Human Clinical

"Erythrokeratodermia variabilis is a rare autosomal-dominant genodermatosis characterized by migratory and erythematous patches changing over the course of hours to days, and fixed keratotic plaques."

Supports the migratory, rapidly changing behavior of the erythematous lesions.

Integument 2

Fixed hyperkeratotic plaques Hyperkeratosis HP:0000962

Show evidence (2 references)

PMID:26945536 SUPPORT Human Clinical

"Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches."

Directly supports fixed hyperkeratotic plaques as a defining disease manifestation.

PMID:12648223 SUPPORT Human Clinical

"Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location."

Supports persistent plaque-like or generalized hyperkeratosis across genetically heterogeneous EKV families.

Palmoplantar keratoderma HP:0000982

Show evidence (2 references)

PMID:26945536 SUPPORT Human Clinical

"Approximately 50% of affected individuals develop palmoplantar keratoderma."

Directly supports palmoplantar keratoderma as a common component of the EKV phenotype.

PMID:25398053 SUPPORT Human Clinical

"Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma."

Supports palmoplantar keratoderma within the GJA1-related branch of the EKV spectrum.

🧬

Genetic Associations

7

GJB3 (Causative)

Gene: GJB3 hgnc:4285 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:9843209 SUPPORT Human Clinical

"We detected heterozygous missense mutations in GJB3 in four EKV families"

Foundational human family evidence establishing GJB3 as a causal EKV gene.

PMID:21564177 SUPPORT Human Clinical

"A novel missense mutation (c.G88A) was found in the human GJB3 gene"

Extends GJB3 causality to recessive EKV.

CGGV:assertion_1d48c959-31d8-44e2-985c-c48921e8f08a-2023-06-01T160000.000Z SUPPORT Other

ClinGen classifies the GJB3-erythrokeratodermia variabilis gene-disease relationship as definitive with autosomal dominant inheritance.

GJB4 (Causative)

Gene: GJB4 hgnc:4286 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:12648223 SUPPORT Human Clinical

"Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls."

Human genetic evidence showing multiple disease-associated GJB4 mutations across unrelated EKV families.

PMID:34717022 SUPPORT Human Clinical

"Our findings reveal an essential role of GJB4 in the pathogenesis of EKVP"

Contemporary support that GJB4 remains an established EKV gene.

GJA1 (Causative)

Gene: GJA1 hgnc:4274 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25398053 SUPPORT Human Clinical

"By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP."

Directly establishes GJA1 as a causal EKV gene.

PMID:25398053 SUPPORT Human Clinical

"The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations."

Supports modeling GJA1-related EKV as a distinct EKV skin phenotype rather than as a side note under ODDD.

KDSR (Causative)

Gene: KDSR hgnc:4021 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:28575652 SUPPORT Human Clinical

"we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum"

Establishes KDSR as causative and identifies the affected pathway.

PMID:28575652 SUPPORT Human Clinical

"Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping."

Source for the allele classes described in this record's notes, including the inversion size and the silent exon-skipping change.

KRT83 (Causative)

Gene: KRT83 hgnc:6460 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:27965375 SUPPORT Human Clinical

"Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."

The genetic evidence for KRT83, and the basis for recording the protein effect as predicted rather than demonstrated.

PMID:27965375 SUPPORT Human Clinical

"At least some cases of PSEK result from loss-of-function mutations in KRT83."

The authors' own hedged conclusion, which is why this record does not present KRT83 as accounting for the whole recessive PSEK group.

TRPM4 (Causative)

Gene: TRPM4 hgnc:17993 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:30528822 SUPPORT Human Clinical

"we report cases of mutations in TRPM4, which encodes TRPM4, a Ca2+-activated monovalent cation channel, as a cause of an autosomal dominant form of progressive symmetric erythrokeratodermia"

Establishes TRPM4 as causative, names the channel type, and gives the dominant transmission of this subtype.

PERP (Causative)

Gene: PERP hgnc:17637 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:30321533 SUPPORT Human Clinical

"Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers."

Establishes PERP as causative for the recessive erythrokeratoderma subtype and states the effect on expression.

PMID:30321533 SUPPORT Human Clinical

"Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma."

Source for describing PERP as a desmosomal component with two disease modes, as this record's features field states.

💊

Medical Actions

1

Acitretin

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

Systemic retinoid therapy may substantially improve hyperkeratosis in some patients, but treatment response is variable and resistance has also been reported.

Show evidence (2 references)

PMID:2150049 SUPPORT Human Clinical

"An initial dose of 35 mg of acitretin and a maintenance dose of 25-35 mg resulted in a pronounced and sustained improvement."

Supports acitretin as an effective systemic retinoid option in at least some EKV patients.

PMID:16854764 SUPPORT Human Clinical

"We present herein a sporadic case with adult onset that was unusually resistant to both isotretinoin and acitretin."

Shows that systemic retinoid response is not uniform, so benefit should be treated as variable rather than universal.

📈

Progression

2

Onset

Age: Birth to infancy

Show evidence (1 reference)

PMID:22266302 SUPPORT Human Clinical

"The onset is usually at birth or during infancy"

Supports typical early-life onset of EKV.

Chronic

Age: Lifelong

Show evidence (1 reference)

PMID:22266302 SUPPORT Human Clinical

"the disease persists throughout life."

Supports chronic persistence of EKV after onset.

{ }

Source YAML

click to show

name: Erythrokeratodermia Variabilis
creation_date: '2026-04-14T05:27:49Z'
category: Mendelian
description: >-
  Erythrokeratodermia variabilis (EKV), also called erythrokeratodermia
  variabilis et progressiva (EKVP) or Mendes da Costa disease, is a rare
  connexin-associated disorder of cornification. The disease is defined by
  transient figurate erythematous patches together with fixed hyperkeratotic
  plaques, often begins at birth or during infancy, and may be accompanied by
  palmoplantar keratoderma. Most reported families show autosomal dominant
  inheritance with incomplete penetrance, although recessive transmission has
  also been described. The disease root is subdivided into a numbered EKVP
  series, and only its first three members are connexinopathies: GJB3 (EKVP1),
  GJB4 (EKVP2) and GJA1 (EKVP3) encode epidermal connexins whose dysfunction
  perturbs keratinocyte gap-junction communication and epidermal homeostasis.
  The remaining four subtypes are not connexin diseases. KDSR (EKVP4) is an
  enzyme of the ceramide synthesis pathway, KRT83 (EKVP5) a hair keratin
  allelic with dominant monilethrix, TRPM4 (EKVP6) a calcium-activated cation
  channel acting by gain of function, and PERP (EKVP7) a desmosomal component
  that also causes Olmsted syndrome through a different allele class. The first
  three of those four were reported as progressive symmetric erythrokeratoderma
  and PERP as widespread erythrokeratoderma, so a reader looking for the classic
  Mendes da Costa picture of migratory patches should read EKVP1 to EKVP3. All
  seven converge on abnormal epidermal homeostasis and keratinization.
synonyms:
- erythrokeratodermia variabilis et progressiva
- Mendes da Costa disease
disease_term:
  preferred_term: erythrokeratodermia variabilis
  term:
    id: MONDO:0017851
    label: erythrokeratodermia variabilis
parents:
- genodermatosis
- Connexinopathy
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    EKV is most often inherited in an autosomal dominant pattern, with marked
    intra- and interfamilial variability and documented incomplete penetrance.
  evidence:
  - reference: PMID:34717022
    reference_title: "Erythrokeratodermia variabilis et progressiva due to a novel mutation in GJB4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of EKVP cases display an autosomal dominant mode of inheritance with incomplete penetrance, although recessive transmission has also been described."
    explanation: Directly supports autosomal dominant inheritance as the major transmission pattern and explicitly notes incomplete penetrance.
  - reference: PMID:9843209
    reference_title: "Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability."
    explanation: Foundational family-based evidence supporting dominant inheritance with variable expression.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Recessive EKV is uncommon but established, particularly in consanguineous
    pedigrees with biallelic GJB3 variants.
  evidence:
  - reference: PMID:21564177
    reference_title: "Erythrokeratoderma variabilis caused by a recessive mutation in GJB3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive inheritance should be considered when providing genetic counselling to consanguineous families at risk for EKV."
    explanation: Directly supports recessive transmission in EKV.
  - reference: PMID:22266302
    reference_title: "Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EKV is mainly inherited as an autosomal dominant disease, although recessive transmission has occasionally been reported."
    explanation: Confirms that recessive inheritance is part of the EKV disease spectrum even though it is less common.
has_subtypes:
- name: EKVP1
  display_name: EKVP1 (GJB3 / connexin 31)
  classification: gene
  description: >-
    Connexin-31 form. Heterozygous GJB3 missense mutations were identified in
    four EKV families, and a recessive GJB3 allele has since been reported in a
    consanguineous pedigree, so this subtype spans both transmission modes.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 1
    term:
      id: MONDO:0033010
      label: erythrokeratodermia variabilis et progressiva 1
  genes:
  - preferred_term: GJB3
    term:
      id: hgnc:4285
      label: GJB3
  evidence:
  - reference: PMID:9843209
    reference_title: "Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected heterozygous missense mutations in GJB3 in four EKV families"
    explanation: >-
      Establishes GJB3 as the gene of the first numbered EKVP subtype in four
      independent families.
- name: EKVP2
  display_name: EKVP2 (GJB4 / connexin 30.3)
  classification: gene
  description: >-
    Connexin-30.3 form, found by sequencing GJB4 in EKV families without a
    detectable GJB3 mutation. Two GJB4 mutations were associated with rapidly
    changing erythematous patches with prominent, circinate or gyrate borders
    in affected children but not in adults.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 2
    term:
      id: MONDO:0033012
      label: erythrokeratodermia variabilis et progressiva 2
  genes:
  - preferred_term: GJB4
    term:
      id: hgnc:4286
      label: GJB4
  evidence:
  - reference: PMID:12648223
    reference_title: "Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls."
    explanation: >-
      Establishes GJB4 as a second connexin gene of the EKVP series in families
      screened because they carried no GJB3 mutation.
  - reference: PMID:12648223
    reference_title: "Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects."
    explanation: >-
      Source for the circinate-border feature stated in this subtype's
      description, including that it was seen in children and not adults.
- name: EKVP3
  display_name: EKVP3 (GJA1 / connexin 43)
  classification: gene
  description: >-
    Connexin-43 form, caused by de novo dominant GJA1 missense mutations. The
    skin disease is reported as distinct from the limited cutaneous findings
    rarely seen in oculodentodigital dysplasia, which dominant GJA1 mutations
    also cause.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 3
    term:
      id: MONDO:0033013
      label: erythrokeratodermia variabilis et progressiva 3
  genes:
  - preferred_term: GJA1
    term:
      id: hgnc:4274
      label: GJA1
  evidence:
  - reference: PMID:25398053
    reference_title: "Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP."
    explanation: >-
      Establishes GJA1 as the third connexin gene of the EKVP series.
- name: EKVP4
  display_name: EKVP4 (KDSR-related, recessive)
  classification: gene
  description: >-
    Recessive ceramide-synthesis form caused by biallelic KDSR mutations. The
    reported phenotype sits in the progressive symmetric erythrokeratoderma
    spectrum rather than the migratory-patch picture of the connexin subtypes:
    severe lesions of thick scaly skin on the face and genitals, and
    thickened, red and scaly skin on the hands and feet. Systemic isotretinoin
    achieved nearly complete resolution in the two probands in whom it was
    applied.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 4
    term:
      id: MONDO:0033014
      label: erythrokeratodermia variabilis et progressiva 4
  genes:
  - preferred_term: KDSR
    term:
      id: hgnc:4021
      label: KDSR
  evidence:
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum"
    explanation: >-
      Establishes biallelic KDSR mutation as a recessive cause in the
      erythrokeratoderma spectrum, and names the affected enzymatic step.
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet."
    explanation: >-
      Source for the lesion distribution given in this subtype's description.
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation."
    explanation: >-
      Source for the isotretinoin response noted in this subtype's description,
      including how many probands were treated.
- name: EKVP5
  display_name: EKVP5 (KRT83-related, recessive)
  classification: gene
  description: >-
    Recessive form attributed to a homozygous KRT83 frameshift deletion in one
    large Pakistani kindred, presenting as progressive symmetric
    erythrokeratoderma. KRT83 is a hair keratin, and heterozygous KRT83
    missense substitutions cause dominant monilethrix, so the two diseases are
    reported as allelic.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 5
    term:
      id: MONDO:0033015
      label: erythrokeratodermia variabilis et progressiva 5
  genes:
  - preferred_term: KRT83
    term:
      id: hgnc:6460
      label: KRT83
  evidence:
  - reference: PMID:27965375
    reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."
    explanation: >-
      The single reported kindred establishing KRT83 as a recessive
      erythrokeratoderma gene, and the basis for calling the allele a predicted
      null rather than a demonstrated one.
  - reference: PMID:27965375
    reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene."
    explanation: >-
      Source for the allelism with monilethrix stated in this subtype's
      description.
- name: EKVP6
  display_name: EKVP6 (TRPM4-related, dominant)
  classification: gene
  description: >-
    Dominant channelopathy form. Two missense mutations in the S6 transmembrane
    domain of TRPM4, found in three separate families with progressive
    symmetric erythrokeratodermia, make the channel hyperactive rather than
    abolishing it, so this is the one EKVP subtype whose reported mechanism is
    a gain of function.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 6
    term:
      id: MONDO:0032801
      label: erythrokeratodermia variabilis et progressiva 6
  genes:
  - preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  evidence:
  - reference: PMID:30528822
    reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three separate families with progressive symmetric erythrokeratodermia, we identified two missense mutations (c.3099C>G and c.3119T>C) that produce p.Ile1033Met and p.Ile1040Thr, both of which are located in the S6 transmembrane domain of the TRPM4 protein."
    explanation: >-
      Establishes TRPM4 as an EKVP-series gene, gives the number of families,
      and locates both alleles in the S6 domain as this description states.
- name: EKVP7
  display_name: EKVP7 (PERP-related, recessive)
  classification: gene
  description: >-
    Recessive desmosomal form. Homozygosity for an N-terminal PERP truncation
    ablates expression and causes widespread erythrokeratoderma. The same gene
    causes Olmsted syndrome when a C-terminal truncation is heterozygous, and
    the reporting authors propose that the two PERP diseases have distinct
    pathobiology rather than differing only in severity.
  subtype_term:
    preferred_term: erythrokeratodermia variabilis et progressiva 7
    term:
      id: MONDO:0030941
      label: erythrokeratodermia variabilis et progressiva 7
  genes:
  - preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers."
    explanation: >-
      Establishes biallelic PERP loss of expression as a cause of widespread
      erythrokeratoderma, which is the EKVP7 phenotype.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."
    explanation: >-
      Source for the statement that a different PERP allele class causes Olmsted
      syndrome, which is why EKVP7 is not the only PERP disease.
progression:
- phase: Onset
  age_range: Birth to infancy
  evidence:
  - reference: PMID:22266302
    reference_title: "Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The onset is usually at birth or during infancy"
    explanation: Supports typical early-life onset of EKV.
- phase: Chronic
  age_range: Lifelong
  evidence:
  - reference: PMID:22266302
    reference_title: "Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the disease persists throughout life."
    explanation: Supports chronic persistence of EKV after onset.
phenotypes:
- category: Dermatological
  name: Transient figurate erythematous patches
  description: >-
    Migratory or figurate erythematous patches are a defining feature of EKV and
    can change location over hours to days.
  phenotype_term:
    preferred_term: transient figurate erythematous patches
    term:
      id: HP:0033622
      label: Migratory erythematous plaque
  evidence:
  - reference: PMID:26945536
    reference_title: "Erythrokeratodermia variabilis et progressiva."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches."
    explanation: Directly supports transient erythematous lesions as a core phenotype of EKV.
  - reference: PMID:16854764
    reference_title: "Erythrokeratodermia variabilis with adult onset: report of a sporadic case unresponsive to systemic retinoids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis is a rare autosomal-dominant genodermatosis characterized by migratory and erythematous patches changing over the course of hours to days, and fixed keratotic plaques."
    explanation: Supports the migratory, rapidly changing behavior of the erythematous lesions.
- category: Dermatological
  name: Fixed hyperkeratotic plaques
  description: >-
    Hyperkeratotic plaques are persistent lesions that may be localized or more
    generalized across the skin.
  phenotype_term:
    preferred_term: fixed hyperkeratotic plaques
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:26945536
    reference_title: "Erythrokeratodermia variabilis et progressiva."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches."
    explanation: Directly supports fixed hyperkeratotic plaques as a defining disease manifestation.
  - reference: PMID:12648223
    reference_title: "Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location."
    explanation: Supports persistent plaque-like or generalized hyperkeratosis across genetically heterogeneous EKV families.
- category: Dermatological
  name: Palmoplantar keratoderma
  description: >-
    Palmoplantar keratoderma occurs in a substantial subset of affected
    individuals and broadens the cutaneous disease burden beyond transient
    erythema and fixed plaques.
  phenotype_term:
    preferred_term: palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:26945536
    reference_title: "Erythrokeratodermia variabilis et progressiva."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 50% of affected individuals develop palmoplantar keratoderma."
    explanation: Directly supports palmoplantar keratoderma as a common component of the EKV phenotype.
  - reference: PMID:25398053
    reference_title: "Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma."
    explanation: Supports palmoplantar keratoderma within the GJA1-related branch of the EKV spectrum.
pathophysiology:
- name: Connexin Mislocalization
  description: >-
    Pathogenic EKV variants disrupt connexin trafficking or membrane
    localization, preventing normal delivery of epidermal connexins to the cell
    surface. Mislocalization has been shown for all three connexin genes of the
    EKVP series - Cx31 (GJB3), Cx30.3 (GJB4) and Cx43 (GJA1) - so this node is
    the shared entry point of the connexin subtypes EKVP1 to EKVP3.
  genes:
  - preferred_term: GJB3
    term:
      id: hgnc:4285
      label: GJB3
  - preferred_term: GJB4
    term:
      id: hgnc:4286
      label: GJB4
  - preferred_term: GJA1
    term:
      id: hgnc:4274
      label: GJA1
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: gap junction channel activity
    term:
      id: GO:0005243
      label: gap junction channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Impaired Gap Junction Assembly
    description: >-
      Loss of membrane-targeted connexins reduces the capacity of keratinocytes
      to form effective epidermal gap junctions.
    evidence:
    - reference: PMID:21564177
      reference_title: "Erythrokeratoderma variabilis caused by a recessive mutation in GJB3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation."
      explanation: Supports a causal link from failed membrane targeting to reduced gap-junction formation.
  evidence:
  - reference: PMID:21564177
    reference_title: "Erythrokeratoderma variabilis caused by a recessive mutation in GJB3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation."
    explanation: Directly shows that a recessive GJB3 EKV mutation disrupts membrane targeting.
  - reference: PMID:30924322
    reference_title: "Two de novo GJA1 mutation in two sporadic patients with erythrokeratodermia variabilis et progressiva."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GJA1 P283L and T290N mutations lead to Cx43 protein cytoplasmic mislocalization."
    explanation: Supports connexin mislocalization as a recurrent mechanism in GJA1-related EKV.
  - reference: PMID:34717022
    reference_title: "Erythrokeratodermia variabilis et progressiva due to a novel mutation in GJB4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "while wild-type GJB4 localized at the cell membrane of HeLa cells forming intercellular junctions and intracellular puncta, V37M mutant variant was diffusely expressed within HeLa cells at a considerably lower level"
    explanation: >-
      Extends the mislocalization mechanism to the third connexin gene bound on
      this node, GJB4, which the other two evidence items do not cover.
- name: Impaired Gap Junction Assembly
  description: >-
    Loss of membrane-targeted connexins reduces keratinocyte participation in
    epidermal gap-junction networks and disrupts intercellular signaling across
    the epidermis.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: gap junction assembly
    term:
      id: GO:0016264
      label: gap junction assembly
    modifier: ABNORMAL
  - preferred_term: cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Abnormal Epidermal Homeostasis and Keratinization
    description: >-
      Loss of effective epidermal gap-junction communication disrupts the
      differentiation programs that normally maintain cutaneous homeostasis.
    evidence:
    - reference: PMID:9843209
      reference_title: "Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors."
      explanation: Supports a causal link from impaired gap-junction communication to downstream defects in epidermal differentiation.
  evidence:
  - reference: PMID:21564177
    reference_title: "Erythrokeratoderma variabilis caused by a recessive mutation in GJB3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation."
    explanation: Directly supports impaired gap-junction formation downstream of connexin mislocalization.
- name: Abnormal Epidermal Homeostasis and Keratinization
  description: >-
    Impaired epidermal differentiation and homeostasis, producing persistent
    hyperkeratosis and episodic erythematous lesions. This is the convergence
    point of every subtype in the entry: the connexin subtypes reach it through
    failed gap-junction communication, and the non-connexin subtypes reach it
    through deficient ceramide synthesis, desmosome immaturity, keratinocyte
    hyperproliferation, or loss of keratin 83.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  - preferred_term: cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:9843209
    reference_title: "Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors."
    explanation: Supports disturbed epidermal differentiation as a core mechanistic consequence of GJB3-mediated EKV.
  - reference: PMID:25398053
    reference_title: "Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1."
    explanation: Supports abnormal epidermal homeostasis as a mechanistic endpoint in the GJA1-related branch of EKV.
  downstream:
  - target: Transient figurate erythematous patches
    description: Disturbed epidermal homeostasis produces episodic figurate erythematous patches.
  - target: Fixed hyperkeratotic plaques
    description: Abnormal keratinization produces persistent hyperkeratotic plaques.
  - target: Palmoplantar keratoderma
    description: Palmoplantar epidermal keratinization defects manifest as palmoplantar keratoderma.
- name: Epidermal Ceramide Synthesis Deficiency
  description: >-
    The EKVP4 route. KDSR catalyses a step of the ceramide synthesis pathway,
    and the reported biallelic EKVP4 alleles were shown by immunohistochemistry
    and yeast complementation to impair KDSR function. Ceramide output is
    therefore reduced rather than merely altered - an inference the isotretinoin
    response supports, since the authors read it as recruitment of alternative
    pathways for ceramide generation.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KDSR
    term:
      id: hgnc:4021
      label: KDSR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: 3-dehydrosphinganine reductase activity
    term:
      id: GO:0047560
      label: 3-dehydrosphinganine reductase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: ceramide biosynthetic process
    term:
      id: GO:0046513
      label: ceramide biosynthetic process
    modifier: DECREASED
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function."
    explanation: >-
      Functional demonstration that the EKVP4 alleles impair the enzyme, which
      is what this node asserts.
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation."
    explanation: >-
      Cited for the directional reading of the node: the authors attribute the
      retinoid response to alternative ceramide generation, which presupposes
      that ceramide output is deficient.
  downstream:
  - target: Abnormal Epidermal Homeostasis and Keratinization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Deficient epidermal ceramide synthesis produces the scaly hyperkeratotic
      phenotype. The steps between the enzymatic defect and the epidermal
      lesion are not characterized in the reporting study.
    evidence:
    - reference: PMID:28575652
      reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet."
      explanation: >-
        Establishes the epidermal phenotype that follows the KDSR defect in the
        reported probands.
- name: TRPM4 Cation Channel Hyperactivity
  description: >-
    The EKVP6 route, and the only gain-of-function mechanism in the entry. Both
    reported alleles sit in the S6 transmembrane domain, where the cryo-EM
    structures predict a direct effect on activation gating, and
    electrophysiology of the mutants shows raised baseline activity, greater
    sensitivity to intracellular Ca2+ and a higher resting membrane potential.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: calcium-activated cation channel activity
    term:
      id: GO:0005227
      label: calcium-activated cation channel activity
    modifier: GAIN_OF_FUNCTION
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:30528822
    reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electrophysiological studies of the mutants showed substantial hyperactivity, as evidenced by pronounced baseline activity, enhanced sensitivity to intracellular Ca2+, and an elevated resting membrane potential."
    explanation: >-
      The measurement behind this node: the mutant channels are hyperactive, not
      merely mislocalized or lost.
  - reference: PMID:30528822
    reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The substitutions are expected to directly affect activation gating of TRPM4 according to the cryo-EM structures."
    explanation: >-
      Structural basis for placing the lesion at the activation gate, which the
      node's description states as a prediction rather than a measurement.
  downstream:
  - target: Keratinocyte Hyperproliferation
    causal_link_type: DIRECT
    description: >-
      Keratinocytes overexpressing either mutant channel proliferate more than
      controls, so channel hyperactivity drives the proliferative state.
    evidence:
    - reference: PMID:30528822
      reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants."
      explanation: >-
        Directly links the mutant channels to increased keratinocyte
        proliferation.
- name: Desmosome Maturation Failure
  description: >-
    The EKVP7 route. Skin from a subject homozygous for the N-terminal PERP
    truncation shows desmosomes lacking the electron-dense midline of mature
    desmosomes, with reduced desmosome numbers and increased fragmentation
    after mechanical stress, while other desmosomal components localize
    normally. The exact function of PERP within the desmosome is not known.
  biological_scale: CELLULAR
  genes:
  - preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: structural molecule activity
    term:
      id: GO:0005198
      label: structural molecule activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: desmosome organization
    term:
      id: GO:0002934
      label: desmosome organization
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress."
    explanation: >-
      The electron-microscopy and dissociation findings in subject skin that
      this node asserts.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins."
    explanation: >-
      Source for restricting the node's claim to desmosome maturation rather
      than to loss of the desmosomal protein complement.
  downstream:
  - target: Abnormal Epidermal Homeostasis and Keratinization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Immature desmosomes and impaired adhesion accompany the widespread
      erythrokeratoderma of EKVP7. The reporting authors state that the exact
      function of PERP in desmosomes is unknown, so the intervening steps are
      not established.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders."
      explanation: >-
        The authors' own summary linking PERP desmosomal function to epidermal
        homeostasis, at the level of certainty this edge claims.
- name: Keratinocyte Hyperproliferation
  description: >-
    Increased keratinocyte proliferation, reported for both non-connexin
    dominant and recessive routes in this entry: keratinocytes overexpressing
    either mutant TRPM4 channel show enhanced proliferation, and skin from both the
    dominant and recessive PERP subjects is hyperproliferative. Only TRPM4 carries
    a downstream edge into this node. The PERP route reaches it through the gene
    binding alone, because the PERP report establishes that the skin is
    hyperproliferative without establishing whether that follows the desmosome
    maturation failure or accompanies it.
  biological_scale: CELLULAR
  genes:
  - preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  - preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:30528822
    reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants."
    explanation: >-
      The TRPM4 arm of this node's claim, measured in cultured keratinocytes.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress."
    explanation: >-
      The PERP arm of this node's claim, observed in subject skin.
  downstream:
  - target: Abnormal Epidermal Homeostasis and Keratinization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Increased keratinocyte proliferation accompanies the up-regulation of
      proliferation and differentiation markers seen in affected skin, and
      contributes to the hyperkeratotic phenotype.
    evidence:
    - reference: PMID:30528822
      reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also detected an up-regulation of markers for proliferation and differentiation of keratinocytes in the affected skin tissues."
      explanation: >-
        Shows the proliferative and differentiation change together in affected
        skin, which is the link this edge asserts.
- name: Keratin 83 Loss of Function
  description: >-
    The EKVP5 route, and the least characterized. The single reported kindred
    carries a homozygous KRT83 frameshift that the authors state is expected to
    abolish keratin 83, a type II keratin of hair and skin. That expectation is
    the whole of the molecular claim available, so this node records a predicted
    null and asserts nothing about how it reaches the epidermis.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KRT83
    term:
      id: hgnc:6460
      label: KRT83
  molecular_functions:
  - preferred_term: structural constituent of cytoskeleton
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
    modifier: LOSS_OF_FUNCTION
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:27965375
    reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."
    explanation: >-
      The whole basis of this node: a co-segregating frameshift whose protein
      effect is stated as an expectation.
  downstream:
  - target: Abnormal Epidermal Homeostasis and Keratinization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of keratin 83 co-segregates with the progressive symmetric
      erythrokeratoderma phenotype. The authors' own conclusion is hedged to
      "at least some cases", and no intervening epidermal mechanism is reported.
    evidence:
    - reference: PMID:27965375
      reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At least some cases of PSEK result from loss-of-function mutations in KRT83."
      explanation: >-
        The hedge is quoted deliberately: it is the strongest statement the
        source makes about this edge.
genetic:
- name: GJB3
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP1
  gene_term:
    preferred_term: GJB3
    term:
      id: hgnc:4285
      label: GJB3
  notes: >-
    GJB3 is a foundational EKV gene with both dominant and recessive disease
    alleles reported.
  evidence:
  - reference: PMID:9843209
    reference_title: "Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected heterozygous missense mutations in GJB3 in four EKV families"
    explanation: Foundational human family evidence establishing GJB3 as a causal EKV gene.
  - reference: PMID:21564177
    reference_title: "Erythrokeratoderma variabilis caused by a recessive mutation in GJB3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel missense mutation (c.G88A) was found in the human GJB3 gene"
    explanation: Extends GJB3 causality to recessive EKV.
  - reference: CGGV:assertion_1d48c959-31d8-44e2-985c-c48921e8f08a-2023-06-01T160000.000Z
    reference_title: "GJB3 / erythrokeratodermia variabilis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GJB3 | HGNC:4285 | erythrokeratodermia variabilis | MONDO:0017851 | AD | Definitive"
    explanation: ClinGen classifies the GJB3-erythrokeratodermia variabilis gene-disease relationship as definitive with autosomal dominant inheritance.
- name: GJB4
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP2
  gene_term:
    preferred_term: GJB4
    term:
      id: hgnc:4286
      label: GJB4
  notes: >-
    GJB4 explains a genetically heterogeneous subset of EKV and appears
    particularly associated with some annular or rapidly changing erythematous
    patterns.
  evidence:
  - reference: PMID:12648223
    reference_title: "Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls."
    explanation: Human genetic evidence showing multiple disease-associated GJB4 mutations across unrelated EKV families.
  - reference: PMID:34717022
    reference_title: "Erythrokeratodermia variabilis et progressiva due to a novel mutation in GJB4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings reveal an essential role of GJB4 in the pathogenesis of EKVP"
    explanation: Contemporary support that GJB4 remains an established EKV gene.
- name: GJA1
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP3
  gene_term:
    preferred_term: GJA1
    term:
      id: hgnc:4274
      label: GJA1
  notes: >-
    GJA1-related EKV is a skin-predominant branch of the EKV disease root and
    should not be collapsed into oculodentodigital dysplasia.
  evidence:
  - reference: PMID:25398053
    reference_title: "Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP."
    explanation: Directly establishes GJA1 as a causal EKV gene.
  - reference: PMID:25398053
    reference_title: "Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations."
    explanation: Supports modeling GJA1-related EKV as a distinct EKV skin phenotype rather than as a side note under ODDD.
- name: KDSR
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP4
  gene_term:
    preferred_term: KDSR
    term:
      id: hgnc:4021
      label: KDSR
  features: >-
    KDSR encodes 3-ketodihydrosphingosine reductase, an enzyme of the ceramide
    synthesis pathway. Biallelic mutations cause the EKVP4 subtype. This is the
    first non-connexin gene in the series: the lesion is in epidermal lipid
    synthesis rather than in gap-junction communication.
  notes: >-
    The reported alleles include a 346 kb inversion found by genome sequencing
    after exome sequencing had identified other KDSR mutations, and two
    mutations - one a recurrent silent third-base change - that act by causing
    exon skipping.
  evidence:
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum"
    explanation: >-
      Establishes KDSR as causative and identifies the affected pathway.
  - reference: PMID:28575652
    reference_title: "Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping."
    explanation: >-
      Source for the allele classes described in this record's notes, including
      the inversion size and the silent exon-skipping change.
- name: KRT83
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP5
  gene_term:
    preferred_term: KRT83
    term:
      id: hgnc:6460
      label: KRT83
  features: >-
    KRT83 encodes keratin 83, a type II keratin of hair and skin. A homozygous
    frameshift deletion co-segregated with recessive progressive symmetric
    erythrokeratoderma in one large Pakistani kindred; the same gene carries
    heterozygous missense substitutions in dominant monilethrix.
  notes: >-
    Evidence rests on a single reported kindred, and the effect on the protein
    is stated by the authors as an expectation from the frameshift rather than
    as a measured loss. The KRT83 monilethrix side of the allelic relationship
    is curated in this repository under Monilethrix.
  evidence:
  - reference: PMID:27965375
    reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin."
    explanation: >-
      The genetic evidence for KRT83, and the basis for recording the protein
      effect as predicted rather than demonstrated.
  - reference: PMID:27965375
    reference_title: "Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least some cases of PSEK result from loss-of-function mutations in KRT83."
    explanation: >-
      The authors' own hedged conclusion, which is why this record does not
      present KRT83 as accounting for the whole recessive PSEK group.
- name: TRPM4
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP6
  gene_term:
    preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  features: >-
    TRPM4 encodes a Ca2+-activated monovalent cation channel. Two dominant
    missense mutations in the S6 transmembrane domain cause the EKVP6 subtype
    by making the channel hyperactive, so the gene-disease mechanism here is a
    gain of function rather than the loss of function seen in the other
    subtypes.
  notes: >-
    TRPM4 also carries gain-of-function variants causing cardiac conduction
    disease, curated in this repository under Progressive Familial Heart Block.
    A reader comparing the two entries should note that they are different
    diseases of the same channel, not one syndrome.
  evidence:
  - reference: PMID:30528822
    reference_title: "Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report cases of mutations in TRPM4, which encodes TRPM4, a Ca2+-activated monovalent cation channel, as a cause of an autosomal dominant form of progressive symmetric erythrokeratodermia"
    explanation: >-
      Establishes TRPM4 as causative, names the channel type, and gives the
      dominant transmission of this subtype.
- name: PERP
  association: Causative
  relationship_type: CAUSATIVE
  subtype: EKVP7
  gene_term:
    preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  features: >-
    PERP encodes a component of desmosomes. Homozygosity for an N-terminal
    truncation ablates expression and causes the widespread erythrokeratoderma
    of EKVP7; heterozygosity for a C-terminal truncation causes Olmsted
    syndrome instead. Both allele classes produce immature desmosomes and
    impaired intercellular adhesion.
  notes: >-
    The two PERP diseases are allele-class dependent rather than a severity
    gradient. The authors note that the recessive allele's carriers - the
    proband's consanguineous parents - are unaffected, and that PERP
    heterozygous truncating variants occur in control databases, which is their
    argument against haploinsufficiency explaining the dominant disease.
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers."
    explanation: >-
      Establishes PERP as causative for the recessive erythrokeratoderma
      subtype and states the effect on expression.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma."
    explanation: >-
      Source for describing PERP as a desmosomal component with two disease
      modes, as this record's features field states.
treatments:
- name: Acitretin
  description: >-
    Systemic retinoid therapy may substantially improve hyperkeratosis in some
    patients, but treatment response is variable and resistance has also been
    reported.
  evidence:
  - reference: PMID:2150049
    reference_title: "Acitretin in the treatment of erythrokeratodermia variabilis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An initial dose of 35 mg of acitretin and a maintenance dose of 25-35 mg resulted in a pronounced and sustained improvement."
    explanation: Supports acitretin as an effective systemic retinoid option in at least some EKV patients.
  - reference: PMID:16854764
    reference_title: "Erythrokeratodermia variabilis with adult onset: report of a sporadic case unresponsive to systemic retinoids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present herein a sporadic case with adult onset that was unusually resistant to both isotretinoin and acitretin."
    explanation: Shows that systemic retinoid response is not uniform, so benefit should be treated as variable rather than universal.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
notes: >-
  This entry is curated at the disease-root level for MONDO:0017851
  erythrokeratodermia variabilis. It now carries the whole numbered EKVP series
  as has_subtypes rows, each anchored to its own MONDO class: EKVP1
  MONDO:0033010, EKVP2 MONDO:0033012, EKVP3 MONDO:0033013, EKVP4
  MONDO:0033014, EKVP5 MONDO:0033015, EKVP6 MONDO:0032801, EKVP7
  MONDO:0030941. Every one of these is a hierarchical descendant of
  MONDO:0017851 and carries exactly one RO:0004003 gene edge, read from OLS4 in
  September 2026.

  The series is lumped here rather than split into seven entries because MONDO
  files all seven under this root and because all seven converge on the same
  terminal node. That said, the split within it is real and is recorded in each
  subtype's description: EKVP1 to EKVP3 are connexin gap-junction diseases with
  the migratory-patch picture, while EKVP4 to EKVP7 are non-connexin - three of
  them reported as progressive symmetric erythrokeratoderma and PERP as
  widespread erythrokeratoderma. A reader looking for classic Mendes da Costa
  disease should read EKVP1 to EKVP3.

  The published distinction between GJA1-related EKV skin disease and
  oculodentodigital dysplasia is preserved, as is the parallel case of PERP,
  where a C-terminal heterozygous truncation causes Olmsted syndrome rather
  than erythrokeratoderma.

  MONDO:0018853 transgrediens et progrediens palmoplantar keratoderma is the
  eighth hierarchical descendant of this root. It carries no RO:0004003 gene
  edge and no numbered EKVP identity, so it is outside the gene-defined series
  this entry models and is not curated here.

  Orphanet could not be consulted for this entry: references_cache holds no
  ORPHA record for erythrokeratodermia variabilis, and populating one requires
  the gitignored Orphadata bulk XML. The StatPearls chapter (PMID:31082124,
  NBK541080) is listed in the references block for orientation but is not used
  as evidence anywhere in this entry: StatPearls is a point-of-care reference
  and is never a curation baseline in this repository. No GeneReviews chapter
  exists for this disease, confirmed against the committed Bookshelf index via
  just check-genereviews.
references:
- reference: PMID:31082124
  title: "Erythrokeratodermia Variabilis."
  tags:
  - StatPearls
  findings: []

📚

References & Deep Research

References

1

PMID:31082124

Erythrokeratodermia Variabilis.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Erythrokeratodermia Variabilis. Core disease mechanisms, molecular and cel...

Asta Scientific Corpus Retrieval 18 citations 2026-04-13T22:37:16.621741

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Erythrokeratodermia Variabilis. Core disease mechanisms, molecular and cel...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 18
Snippets retrieved: 20

Relevant Papers

[1] Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP)

Authors: A. Terrinoni, G. Sala, Ernesto Bruno, Consuelo Pitolli, M. Minieri et al.
Year: 2023
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/3042ff40f9af1eac025ccb7cdc2e98af65eafc50
DOI: 10.3390/ijms241813962
PMID: 37762265
PMCID: 10530436
Citations: 8
Influential citations: 1
Summary: This study analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV), and demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis.
Evidence snippets:
Snippet 1 (score: 0.457) > Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.
Snippet 2 (score: 0.454) > Eritrokeratodermia variabilis (EKV, OMIM 133200) is another peculiar disease that is caused by defects in the process of keratinization. EKV is a rare, congenital, epithelial disease with early onset, characterized by remitting-relapsing erythematous patches associated with plaques of hyperkeratosis, sometimes massive (hystrix-like), stationary, or migratory [13]. The EKV disease has been associated with mutations in connexin genes GJB3 (Cx31) [14] and GJB4 (CX30.3) [15,16]. Recently, a variant of this disease has been identified, caused by mutations in connexin gene GJA1 (Cx43) [17]. Since it has not been recognized as a distinct entity, the new definition of erythrokeratodermia variabilis et progressiva (EKVP) has now been used to include the GJA1 variant. The accurate prevalence of EKVP is unknown, but it is estimated to be less than 1:200.000, being primarily inherited as an autosomal dominant connexin-dependent disease. Despite its dominant transmission, few cases of recessive transmission have been reported [18][19][20][21]. > The clinical features of EKVP present some overlap with other forms of ichthyoses such as lamellar ichthyosis or epidermolytic hyperkeratosis. Indeed, EKVP can be included within the ichthyosis group of mendelian disorders of cornification (MeDOC) [8], although its clinical phenotype is not characterized by generalized scaling of the epidermis and/or erythema. In addition, EKVP presents histologically with a thinner stratum corneum in respect of the other types of ichthyoses. > Although some of the genetic bases of EKVP have been discovered, the mechanism by which the reported mutations in connexin genes give rise to the general phenotype of the disease is still unclear.

[2] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.451) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[3] The genetic and molecular basis of a connexin-linked skin disease

Authors: Sergiu A. Lucaciu, Dale W Laird
Year: 2024
Venue: Biochemical Journal
URL: https://www.semanticscholar.org/paper/ec98115afd0d803d04f3ed9af4991faa8eebc2a5
DOI: 10.1042/BCJ20240374
PMID: 39513663
PMCID: 11668363
Citations: 5
Summary: Evidence suggests that connexin variants associated with EKVP elicit a plethora of molecular defects including impaired gap junction (GJ) formation, dysregulated hemichannel and/or GJ channel function, cytotoxicity, dominant disruption of co-expressed connexins, and/or altered turnover kinetics.
Evidence snippets:
Snippet 1 (score: 0.440) > Indeed, loricrin gene variants cause a range of phenotypic presentations, including PSEK-like keratodermas, thus the field adopted the terminology of 'loricrin keratoderma' to distinguish this disorder from other similar presenting diseases with distinct molecular etiologies [45]. Furthermore, since as early as 1991, it has been proposed that EKV and PSEK may represent different clinical manifestations of the same condition [46], since the main clinical difference between EKV and PSEK is that EKV lesions are well-demarcated and migratory, while PSEK lesions are nonmigratory and symmetric [34]. It has been argued that the available clinical evidence does not support the existence of a non-migratory PSEK phenotype, rather the migratory erythemas in EKV are sometimes static and increasing in size, resembling the PSEK phenotype [34]. Once evidence emerged that the same GJB4 variant (Cx30.3-G12D) may cause phenotypes consistent with a diagnosis of either EKV or PSEK in the same family, van Steensel and colleagues proposed adopting the new nomenclature of erythrokeratodermia variabilis et progressiva (EKVP) to encompass both the variable and progressive nature of the lesions [34,47]. For simplicity, we will use the term EKVP throughout this paper to collectively refer to these variable clinical manifestations, except in situations where the clinical phenotype demands distinguishing between EKVP and other erythrokeratodermas. > Here, we set out to review the known and putative underlying molecular causes of EKVP associated with connexin gene variants, what is known about the underlying pathogenic mechanisms, the landscape of treatment options, and the pressing questions that need to be addressed.
Snippet 2 (score: 0.395) > Note: the helical NTD inserts into the aqueous pore and is not embedded in the lipid bilayer. (D) Six connexins oligomerize to form a single membrane-spanning channel termed a HC (aka, connexon), with an aqueous pore connecting the cytoplasm and extracellular milieu. > (E) Compatible HCs on opposing cell membranes can dock to form unique double membrane-spanning intercellular channels called GJ channels. The aqueous pore in these channels directly connect the cytoplasm of the adjoined cells. Both types of channels permit the passage of small metabolites and ions up to 1 kDa in size. Created using BioRender. > The crucial roles of these keratinocyte connexins within the epidermis are highlighted by gene ablation/ attenuation studies and the association between connexin-encoding gene mutations and skin disease [25,26]. Variants in the genes encoding five of these keratinocyte connexins are clinically linked to at least seven cutaneous disorders with varying severity including some life-shortening conditions [25,26]. However, not all gene variants result in skin phenotypes, as Cx26 gene variants are the most common cause of sensorineural hearing loss that can occur with or without skin manifestations in a variant-dependent manner [26,27]. Similarly, the vast majority of Cx43 variants cause oculodentodigital dysplasia (ODDD), a rare congenital condition impacting various systems that rarely present with skin phenotypes [26,28,29]. > Erythrokeratodermia variabilis (EKV) first described by da Costa in 1925 [30] is a rare hereditary skin disorder characterized by well-demarcated lesions consisting of fixed hyperkeratotic plaques and transient migratory erythematous patches that tend to progressively worsen with age [31]. This classical EKV phenotype is sometimes referred to as EKV of Mendes da Costa, while a similar clinical presentation with distinct circinate erythematous lesions is termed EKV Cram-Mevorah [32,33].

[4] Topical Treatments for Rare Genetic Dermatological Diseases: A Narrative Review

Authors: B. Oliveira, Ana Torres, Eduardo Ricci-Júnior, I. F. Almeida, M. Monteiro
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/dffc2b1f6280306c0db43e826542f92a4d31b340
DOI: 10.3390/ph18111762
PMID: 41305004
PMCID: 12655290
Summary: A comprehensive review of the topical treatments of EB, ichthyosis, HHD, DD, erythrokeratodermias, porokeratosis, ILVEN, and piebaldism highlighted the potential of off-label use of topical therapies as cost-effective alternatives in the treatment of rare genetic skin disorders.
Evidence snippets:
Snippet 1 (score: 0.430) > Erythrokeratodermias are a group of rare genodermatoses characterized by the presence of hyperkeratotic plaques associated with areas of erythema (Figure 1). These conditions exhibit both clinical and genetic heterogeneity and are classified into two main subtypes: Progressive Symmetrical Erythrokeratoderma (PSEK) and Erythrokeratoderma Variabilis (EKV) [42,43]. > PSEK begins in childhood and presents as non-migratory, symmetrical, erythematous, hyperkeratotic plaques. These lesions range in color from reddish orange to brown and show marked peripheral erythema. A typical sign is the symmetry of the lesions, which affect the knees, elbows, hands, and feet [43]. Genetically, PSEK shows considerable phenotypic variability and is predominantly congenital in an autosomal dominant manner. > Although its pathophysiology is not fully understood, mutations in the LOR gene, located on chromosome 1q21, have been identified in some cases. The LOR gene involves loricrin, a structural protein of the cornified cell envelope, a highly resistant protective layer formed in epidermal cells during keratinization. Loricrin plays a fundamental role in the skin barrier, being one of the main proteins that contribute to skin rigidity and impermeability. It is also involved in the formation of keratohyalin granules, structures found in the granular layer of the epidermis that assist in organizing and compacting proteins during the cornification process [43,44]. > EKV is distinguished by the combination of two types of skin lesions: fixed, welldemarcated, symmetrical hyperkeratotic plaques that persist in specific areas, and transient, migratory erythema that shifts location over the course of hours or days. These manifestations may occur simultaneously or alternate throughout an individual's lifetime. The disease typically begins in childhood, although late-onset cases have been reported. Facial involvement, especially on the cheeks is common, as is the involvement of flexural areas such as the axillae, groin, neck, and trunk [42]. EKV exhibits marked phenotypic variability, even among members of the same family.

[5] Role of Transcriptomics in Precision Oncology

Authors: Ruby Srivastava
Year: 2024
Venue: Reports of Radiotherapy and Oncology
URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
DOI: 10.5812/rro-142195
Citations: 4
Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
Evidence snippets:
Snippet 1 (score: 0.399) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[6] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.394) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[7] Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data

Authors: Kinza Rian, Marta R. Hidalgo, C. Çubuk, M. M. Falco, C. Loucera et al.
Year: 2021
Venue: Computational and Structural Biotechnology Journal
URL: https://www.semanticscholar.org/paper/af786ba590cb9db62ff31318c785685ade68bfd9
DOI: 10.1016/j.csbj.2021.05.022
PMID: 34136096
PMCID: 8170118
Citations: 10
Summary: This work presents the implementation of a mechanistic model of cell signaling for the interpretation of transcriptomic data as an R/Bioconductor package, a Cytoscape plugin and a web tool with enhanced functionality which includes building interpretable predictors, estimation of the effect of perturbations and assessment of the effects of mutations in complex scenarios.
Evidence snippets:
Snippet 1 (score: 0.387) > Mechanistic models of signaling pathways provide a natural bridge from variations in genotype (at the scale of gene activity or integrity) to variations in phenotype (at the scale of cells, tissues or organisms) [1]. They are built over graphs that represent the biological knowledge of the complex functional relationships among proteins within the cell, as described in repositories such as KEGG [2], Reactome [3], WikiPathways [4], or other more specialized, such as Disease Maps [5]. Specifically, they provide a conceptual framework for the interpretation of gene expression or genomic variation data and their consequences over downstream processes and phenotypic responses, such as cell proliferation and death, which are particularly relevant for studying disease progression or drug response [6]. Mechanistic models have successfully been used to understand the disease mechanisms behind different cancers [7,8] (including neuroblastoma [9,10] and glioblastoma [11]) rare diseases [12,13], complex diseases such as diabetes [14] or obesity [15], the mechanisms of action of drugs [16] or gender-specific effects of drugs in cancer [17]. In addition to diseases, other scenarios have been studied, such as the molecular mechanisms of death and the post-mortem ischemia of a tissue [18] or the effects of nanoplastics on embryos and human induced pluripotent stem cells [19]. > One of the most important aspects of mechanistic models is that they convey the notion of causality and can, therefore, be used to predict the downstream consequences of perturbations of specific conditions [20]. Thus, the possibility of simulating the effect of a drug allowed a systematic in silico drug repurposing experiment in Fanconi Anemia [21] in which some of the drugs predicted were further validated [22]. Also recently, all the targeted drugs currently in clinical trials for testing treatment and prevention of COVID-19 [23] were predicted by means of a mechanistic model [24] of the COVID-19 disease map [25]. application of mechanistic modeling show how the simulation of drug inhibitions at single-cell level uncovers the molecular basis of the generation of resistance to

[8] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

Authors: I. Condò
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
DOI: 10.3390/ijms23126525
PMID: 35742964
PMCID: 9223693
Citations: 15
Influential citations: 2
Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
Evidence snippets:
Snippet 1 (score: 0.381) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[9] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.381) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[10] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

Authors: Michael Harris, K. Bhuvaneshwar, Thanemozhi Natarajan, L. Sheahan, Difei Wang et al.
Year: 2013
Venue: Pharmacogenetics and Genomics
URL: https://www.semanticscholar.org/paper/1382ddf84b87736a73c2f2f81164ca876c29f4c4
DOI: 10.1097/FPC.0000000000000015
PMID: 24401833
PMCID: 3888473
Citations: 16
Summary: This in-silico study identified gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic and gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews.
Evidence snippets:
Snippet 1 (score: 0.380) > Understanding the genetic and molecular mechanisms underlying complex diseases such as cancer is extremely challenging. Genome-wide association studies (GWAS) have been extensively used in the past decade to discover important genetic variants. However, the identified SNPs explain only a small proportion of the phenotypic variation, and the predictive power of these SNPs remains low for many complex diseases [10]. To fully elucidate genetic underpinnings of disease a systems biology approach is necessary to characterize variants, mRNA, copy number, proteins, and metabolites, as well as their cellular interactions [11]. Gene set and pathway association analyses are playing an increasingly important role in explaining disease mechanisms through the identification of functional genetic interactions [12]. Many gene-disease association analyses are based on SNP genotype profiling or gene expression studies. However, SNPs can influence many downstream processes including the expression levels of multiple genes and/or protein levels, and variations in expression levels can directly or indirectly impact disease progression and even drug response [13]. An integrative approach combining multiple data types can more accurately capture pathway associations [12] for discovery of clinically actionable variants. > Statistical approaches commonly used to associate variants with disease and/or drug response Fisher's exact test (FET) is commonly used in the association of germline polymorphisms with drug response [14]. The use of probabilistic networks in conjunction with traditional statistical models for mining relationships and associations from genotype-phenotype data is well established [15]. Probabilistic network methods for pharmacogenomics and newer methods such as the Markov Blanket concept may be helpful to better analyze these complex genotype-phenotype associations [16]. Considering the complexity of both cancer prognosis and individual drug response to chemotherapeutics, application of these association methods in conjunction with novel informatics and data integration approaches is necessary to identify clinically relevant variants for validation studies and ultimately testing in the clinic for pharmacogenomics applications.

[11] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
Year: 2021
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
DOI: 10.1002/mgg3.1809
PMID: 34519438
PMCID: 8580094
Citations: 12
Influential citations: 2
Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
Evidence snippets:
Snippet 1 (score: 0.377) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[12] Molecular genetic basis of epidermolysis bullosa

Authors: Y. Kotalevskaya, V. Stepanov
Year: 2023
Venue: Vavilov Journal of Genetics and Breeding
URL: https://www.semanticscholar.org/paper/720cbefbd0435504a6ed670ccf4f491dfbd3f143
DOI: 10.18699/VJGB-23-04
PMID: 36923479
PMCID: 10009482
Citations: 8
Influential citations: 2
Summary: The study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the Disease.
Evidence snippets:
Snippet 1 (score: 0.377) > Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB.

[13] Novel insights into the evolution and structural characterization of dyskerin using comprehensive bioinformatics analysis.

Authors: C. Cerrudo, D. M. Mengual Gómez, D. Gomez, P. Ghiringhelli
Year: 2015
Venue: Journal of proteome research
URL: https://www.semanticscholar.org/paper/c8becabfeb8bdbc8ed150b3de31ac69a4cc5a8f9
DOI: 10.1021/pr500956k
PMID: 25540932
Citations: 7
Influential citations: 1
Summary: This work predicted protein domains and compared sequences and structures to detect the universe of dyskerin-like proteins and identified conserved features of shared domains in the three superkingdoms, confirming that there is a strong structural conservation.
Evidence snippets:
Snippet 1 (score: 0.377) > Rocchi et al. have recently created a homology model of human dyskerin by using a template crystal structure from Saccharomyces cerevisiae (PDB ID: 3U28), which has a sequence identity of 73% with the human dyskerin sequence. 9However, the structures of eukaryotic dyskerins remain poorly understood. > A number of related genetic diseases are caused by defects in the telomere maintenance machinery.These disorders, often called telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease.Defects in genes involved in telomere maintenance result in a large overlapping spectrum of symptoms.The best known of these diseases is dyskeratosis congenital disorder (DKC), 10 aplastic anemia, Hoyeraal− Hreidarsson syndrome, idiopathic pulmonary fibrosis, 11 and cancer.The symptoms of these disorders are extensive, and the age of onset is highly variable; however, the disorders share similar underlying molecular mechanisms and have overlapping, incompletely penetrant phenotypes.Recently, an increasing number of reports have identified syndromes that do not include the classic symptoms but are still caused by mutations in core telomere maintenance proteins such as Revesz syndrome and Coats plus syndrome. 12Despite this heterogeneity it is important to go a bit deeper in the role of dyskerin in cancer due to the incidence and mortality of this disease and the fact that dyskerin has been explored for the development of drugs to selectively or preferentially kill cancer cells.A pioneer study has reported dyskerin expression to be increased in several human cancer types, especially in breast cancers. 13In accord with the known biological functions of the protein, breast cancers with low dyskerin expression contained lower levels of pseudouridine and telomerase RNA than those with high expression.Moreover, cancers with high expression generally exhibited worse histopathological features and prognosis.In line with these findings, DKC1 overexpression is associated with prostate cancer progression. 14Also, DKC1 is downregulated in sporadic chronic lymphocytic leukemia. 15

[14] Significance and Mechanisms Analyses of RB1 Mutation in Bladder Cancer Disease Progression and Drug Selection by Bioinformatics Analysis

Authors: Dingguo Zhang, Jinjun Tian, Qier Xia, Zhenyu Yang, B. Gu
Year: 2021
Venue: Bladder Cancer
URL: https://www.semanticscholar.org/paper/6038af24d56f6d9c5eeb1572c64dd5acd6aa62f2
DOI: 10.3233/BLC-200368
PMID: 38994537
PMCID: 11181786
Citations: 7
Summary: The significance of RB1 mutation in disease progression and drug selection in bladder cancer was suggested by the results, and multiple genes and pathways related to such a program were identified.
Evidence snippets:
Snippet 1 (score: 0.376) > Early and comprehensive intervention might be important for such patients to live longer. > Nowadays, molecular pathological diagnosis and individualized medicine testing can help doctors select target drugs according to the characteristics of the patient's tumor cells, including bladder cancer. Different patients may have tumor cells with different pathways activated in their bodies, which results in different molecular and pathological characteristics. These are the main mechanisms for disease progression and drug resistance in many tumors, which is also the basis of individualized treatment. Analyzing the activation of different pathways can help us understand the characteristics of different subtypes of tumors, and might help us explore potential personalized treatment at the same time. If a certain pathway is specifically activated in certain subtype patients, the drugs targeted this pathway might be more effective in such patients. Through these analyses, we can find out the potential mechanisms of drug resistance and clinical phenotypes that are associated with RB1 mutation, and provide some theoretical basis and directions for further research and verification. This might be quite preliminary and only have some theoretical functions. To explore these issues deeply, the gene expression data was analyzed in depth to find the key pathways and core genes associated with RB1 mutation. Results of GSEA analysis suggested that RB1 mutation were mainly associated with DNA repair, multiple cancer related pathways, cell proliferation and division, and metabolism. Previous researches have shown that defects in DNA repair contributed the disease progression of bladder cancer and influenced the treatment, especially in MIBC. Genomic alterations in the DNA repairassociated genes could render tumors sensitive to cisplatin-based chemotherapy for MIBC [20]. RB1 regulates the cell cycle. In RB1 mutated tumors, our findings showed that many processes involved in cell proliferation were enriched. RB1 mutation could result in abnormal regulation of cell cycle and cell division proliferation, which lead to continuous cell growth and tumor progression. Therefore, besides the three drugs above, other drugs, such as Docetaxel (Taxotere) which effectively induces G2M arrest and apoptosis might be more sensitive in patients with RB1 mutation [21]. > Next, we searched for DEGs and performed functional enrichment analysis on them. The results show a total of 999 DEGs. Enrichment analysis suggested that DEGs in RB1 mutated bladder cancer patients implicated with multiple cellular programs.

[15] Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34)

Authors: P. Bourque, J. Warman-Chardon, D. Lelli, L. Laberge, Carly Kirshen et al.
Year: 2018
Venue: Neurology: Genetics
URL: https://www.semanticscholar.org/paper/45cefba2abf5bfb40cebb10bff8a2c4ee695de40
DOI: 10.1212/NXG.0000000000000263
PMID: 30065956
PMCID: 6066365
Citations: 31
Influential citations: 6
Summary: The majority of patients with EK have no pathogenic mutations in the GJB genes or LOR, and there is significant overlap in the clinical and genetic features of the “variabilis” and “progressiva” forms of EK.
Evidence snippets:
Snippet 1 (score: 0.376) > Erythrokeratodermia (EK) is a rare skin disorder, likely genetic and usually present from infancy.1 There is patchy symmetrical involvement over the body surface, manifested in progressive figurate plaques of hyperkeratosis and more transient areas of erythema. There is significant overlap in the clinical and genetic features of the “variabilis” and “progressiva” forms of EK. Restricted cutaneous syndromes of EK have been described associated with mutations in the connexin (GJB3, GJB4, and GJA1) and loricrin (LOR) genes. The majority of patients with EK, however, have no pathogenic mutations in the GJB genes or LOR.

[16] Molecular Genetics of Keratinization Disorders – What’s New About Ichthyosis

Authors: J. Uitto, L. Youssefian, A. Saeidian, H. Vahidnezhad
Year: 2020
Venue: Acta Dermato-Venereologica
URL: https://www.semanticscholar.org/paper/bf6faf053470c47d9da1767b5e76ef97ac78c431
DOI: 10.2340/00015555-3431
PMID: 32147742
PMCID: 9128965
Citations: 27
Influential citations: 2
Summary: Some of the recent progress made in understanding the molecular genetics of keratinization disorders are highlighted, and selected, recently characterized cases are presented as representative of different forms of heritable ichthyosis.
Evidence snippets:
Snippet 1 (score: 0.376) > Erythrokeratoderma manifests with hyperkeratotic, often transient and migratory erythematous and figurate plaques with sharply demarcated borders typically developing in early childhood (Fig. 7). It has been historically divided into two main categories: (a) erythrokeratodermia variabilis et progressiva; and (b) progressive symmetric erythrokeratoderma. However, these two presentations are currently listed on the OMIM catalogue under a single disease entry (OMIM #133200). There are a number of other presentations with erythrokeratoderma (59). Erythrokeratoderma can be inherited either in an autosomal dominant or an autosomal recessive pattern. The autosomal dominant forms have been associated with mutations in the gap junction-related genes (GJB2, GJB3, GJB4, and GJA1) as well as in LOR, encoding loricrin, a cornified envelope protein (53)(54)(55)59). Autosomal recessive erythrokeratoderma has been associated with mutations in ABHD5, ELOVL4 and KDSR. More recently, the genotypic spectrum of erythrokeratoderma has been extended by application of NGS using ichthyosis-associated gene sequencing panels which identified mutations in addition to those previously identified genes, also in PNPLA1 in families with the autosomal recessive form of erythrokeratoderma (Fig. 7) (10). These studies provide evidence in support of the notion that erythrokeratoderma can be a manifestation associated with multiple types of ichthyosis with different gene defects (60). Consequently, erythrokeratoderma may not be a distinct genetic entity but rather a manifestation of multiple ichthyosis-related genetic diseases that can occur with or without a more typical ichthyosis presentation.

[17] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
Year: 2022
Venue: Frontiers in Medical Technology
URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
DOI: 10.3389/fmedt.2022.810315
PMID: 35281671
PMCID: 8907708
Citations: 6
Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
Evidence snippets:
Snippet 1 (score: 0.375) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[18] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.375) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

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Erythrokeratodermia Variabilis

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Erythrokeratodermia Variabilis. Core disease mechanisms, molecular and cel...

Relevant Papers

[1] Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP)

[2] New therapeutic targets in rare genetic skeletal diseases

[3] The genetic and molecular basis of a connexin-linked skin disease

[4] Topical Treatments for Rare Genetic Dermatological Diseases: A Narrative Review

[5] Role of Transcriptomics in Precision Oncology

[6] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

[7] Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data

[8] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

[9] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

[10] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

[11] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

[12] Molecular genetic basis of epidermolysis bullosa

[13] Novel insights into the evolution and structural characterization of dyskerin using comprehensive bioinformatics analysis.

[14] Significance and Mechanisms Analyses of RB1 Mutation in Bladder Cancer Disease Progression and Drug Selection by Bioinformatics Analysis

[15] Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34)

[16] Molecular Genetics of Keratinization Disorders – What’s New About Ichthyosis

[17] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

[18] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Notes