Diffuse nonepidermolytic palmoplantar keratoderma

Summary

Diffuse nonepidermolytic palmoplantar keratoderma (MONDO:0010962) is a disease caused by KRT1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KRT1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diffuse nonepidermolytic palmoplantar keratoderma
Mondo ID	MONDO:0010962
OMIM	600962
Orphanet	496, 530838
DOID	DOID:0050428, DOID:0070550
SNOMED CT	716105001
UMLS	C1833030
MedGen	371463
GARD	0005186
Is cancer (heuristic)	no

Also known as: autosomal dominant diffuse palmoplantar keratoderma, Norrbotten type · diffuse NEPPK · diffuse nonepidermolytic palmoplantar keratoderma · diffuse palmoplantar keratoderma, Bothnian type · KRT1-related diffuse nonepidermolytic keratoderma · NEPPK · non-epidermolytic palmoplantar keratoderma · nonepidermolytic palmoplantar keratoderma · palmoplantar keratoderma, nonepidermolytic · PPK diffusa circumscripta · PPKNE · Thost-Unna disease · Thost-Unna palmoplantar keratoderma · Thost-Unna syndrome · Unna-Thost palmoplantar keratoderma · Unna-Thost syndrome

Data availability: 45 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › diffuse nonepidermolytic palmoplantar keratoderma

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

45 retrieved; paginated sample, class counts are floors:

15 benign, 13 uncertain significance, 9 benign/likely benign, 4 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
15910	NM_006121.4(KRT1):c.221A>T (p.Lys74Ile)	KRT1	Pathogenic	no assertion criteria provided
432078	NM_006121.4(KRT1):c.1453C>T (p.Leu485Phe)	KRT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4686620	NM_006121.4(KRT1):c.1255-1G>T	KRT1	Pathogenic	criteria provided, single submitter
66622	NM_006121.4(KRT1):c.1376_1399del (p.Ala459_Gln466del)	KRT1	Pathogenic	no assertion criteria provided
66657	NM_006121.4(KRT1):c.591+2T>A	KRT1	Pathogenic	no assertion criteria provided
309636	NM_006121.4(KRT1):c.1912A>G (p.Thr638Ala)	KRT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309648	NM_006121.4(KRT1):c.982A>T (p.Thr328Ser)	KRT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805520	NM_006121.4(KRT1):c.48_49insAC (p.Phe17fs)	KRT1	Uncertain significance	criteria provided, single submitter
1805617	NM_006121.4(KRT1):c.1318G>A (p.Ala440Thr)	KRT1	Uncertain significance	criteria provided, single submitter
309631	NM_006121.4(KRT1):c.*372G>A	KRT1	Uncertain significance	criteria provided, single submitter
309633	NM_006121.4(KRT1):c.*275G>A	KRT1	Uncertain significance	criteria provided, single submitter
309652	NM_006121.4(KRT1):c.477G>C (p.Gln159His)	KRT1	Uncertain significance	criteria provided, single submitter
309653	NM_006121.4(KRT1):c.374G>A (p.Gly125Asp)	KRT1	Uncertain significance	criteria provided, single submitter
309655	NM_006121.4(KRT1):c.257G>A (p.Arg86His)	KRT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
881053	NM_006121.4(KRT1):c.1666G>A (p.Gly556Ser)	KRT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
881054	NM_006121.4(KRT1):c.1564G>A (p.Gly522Ser)	KRT1	Uncertain significance	criteria provided, single submitter
881095	NM_006121.4(KRT1):c.1002T>C (p.Asn334=)	KRT1	Uncertain significance	criteria provided, single submitter
881567	NM_006121.4(KRT1):c.729C>T (p.Asp243=)	KRT1	Uncertain significance	criteria provided, single submitter
883407	NM_006121.4(KRT1):c.*72G>T	KRT1	Uncertain significance	criteria provided, single submitter
883452	NM_006121.4(KRT1):c.1358A>C (p.Gln453Pro)	KRT1	Uncertain significance	criteria provided, single submitter
309632	NM_006121.4(KRT1):c.*344C>T	KRT1	Benign	criteria provided, multiple submitters, no conflicts
309634	NM_006121.4(KRT1):c.*95G>A	KRT1	Benign	criteria provided, single submitter
309635	NM_006121.4(KRT1):c.*91T>C	KRT1	Benign	criteria provided, single submitter
309637	NM_006121.4(KRT1):c.1898A>G (p.Lys633Arg)	KRT1	Benign	criteria provided, multiple submitters, no conflicts
309638	NM_006121.4(KRT1):c.1677C>T (p.Tyr559=)	KRT1	Benign	criteria provided, single submitter
309639	NM_006121.4(KRT1):c.1669A>G (p.Ser557Gly)	KRT1	Benign	criteria provided, multiple submitters, no conflicts
309640	NM_006121.4(KRT1):c.1527C>T (p.His509=)	KRT1	Benign/Likely benign	criteria provided, single submitter
309641	NM_006121.4(KRT1):c.1506T>C (p.Ser502=)	KRT1	Benign	criteria provided, multiple submitters, no conflicts
309642	NM_006121.4(KRT1):c.1482T>C (p.Ser494=)	KRT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
309643	NM_006121.4(KRT1):c.1475+14G>A	KRT1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KRT1	Strong	Autosomal dominant	diffuse nonepidermolytic palmoplantar keratoderma	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT1	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT1	Orphanet:281139	Annular epidermolytic ichthyosis
KRT1	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT1	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT1	Orphanet:50942	Striate palmoplantar keratoderma
KRT1	Orphanet:530838	KRT1-related diffuse nonepidermolytic keratoderma
KRT1	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
KRT1	Orphanet:79503	Ichthyosis hystrix of Curth-Macklin

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT1	HGNC:6412	ENSG00000167768	P04264	Keratin, type II cytoskeletal 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT1	Keratin, type II cytoskeletal 1	May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT1	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mammalian vulva	1
skin of hip	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT1	177	tissue_specific	marker	mammalian vulva, upper leg skin, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT1	2,716

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT1	P04264	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of FXIIa and plasma kallikrein activity	1	1142.0×	0.009	KRT1
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.014	KRT1
Developmental Cell Lineages	1	223.9×	0.014	KRT1
FXIIa activates plasma kallikrein-kinin system	1	173.0×	0.014	KRT1
Formation of the cornified envelope	1	87.8×	0.023	KRT1
Keratinization	1	55.7×	0.030	KRT1
Innate Immune System	1	25.5×	0.054	KRT1
Neutrophil degranulation	1	23.1×	0.054	KRT1
Developmental Biology	1	14.5×	0.077	KRT1
Immune System	1	13.0×	0.077	KRT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
complement activation, lectin pathway	1	1685.2×	0.003	KRT1
protein heterotetramerization	1	1053.2×	0.003	KRT1
cornification	1	1053.2×	0.003	KRT1
fibrinolysis	1	842.6×	0.003	KRT1
establishment of skin barrier	1	455.5×	0.004	KRT1
regulation of angiogenesis	1	421.3×	0.004	KRT1
intermediate filament organization	1	240.7×	0.005	KRT1
keratinization	1	234.1×	0.005	KRT1
negative regulation of inflammatory response	1	137.0×	0.008	KRT1
response to oxidative stress	1	130.6×	0.008	KRT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KRT1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.