palmoplantar keratoderma, Bothnian type

Summary

palmoplantar keratoderma, Bothnian type (MONDO:0010849) is a disease caused by AQP5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: AQP5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.5	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0007447	Diffuse palmoplantar kyperkeratosis	Very frequent (80-99%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0008066	Abnormal blistering of the skin	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0032259	Chronic tinea infection	Frequent (30-79%)
HP:0032541	Knuckle pad	Frequent (30-79%)
HP:0200034	Papule	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0001807	Ridged nail	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	palmoplantar keratoderma, Bothnian type
Mondo ID	MONDO:0010849
OMIM	600231
Orphanet	2337
DOID	DOID:0111707
UMLS	C1838359
MedGen	325011
GARD	0001862
Is cancer (heuristic)	no

Also known as: palmoplantar keratoderma, Bothnian type · PPKB

Data availability: 7 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › palmoplantar keratoderma, Bothnian type

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

7 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
65478	NM_001651.4(AQP5):c.113C>A (p.Ala38Glu)	AQP5	Pathogenic	criteria provided, single submitter
65480	NM_001651.4(AQP5):c.134T>G (p.Ile45Ser)	AQP5	Pathogenic	no assertion criteria provided
65481	NM_001651.4(AQP5):c.529A>T (p.Ile177Phe)	AQP5	Pathogenic	no assertion criteria provided
65482	NM_001651.4(AQP5):c.367A>G (p.Asn123Asp)	AQP5	Pathogenic	no assertion criteria provided
1172766	NM_001651.4(AQP5):c.526G>A (p.Gly176Arg)	AQP5	Likely pathogenic	criteria provided, single submitter
1645185	NM_001651.4(AQP5):c.4AAG[1] (p.Lys3del)	AQP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
65479	NM_001651.4(AQP5):c.562C>T (p.Arg188Cys)	AQP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
AQP5	Strong	Autosomal dominant	palmoplantar keratoderma, Bothnian type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AQP5	Orphanet:2337	Diffuse palmoplantar keratoderma, Bothnian type

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
AQP5	HGNC:638	ENSG00000161798	P55064	Aquaporin-5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AQP5	Aquaporin-5	Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.

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)
AQP5	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like

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
left testis	1
olfactory segment of nasal mucosa	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AQP5	176	tissue_specific	marker	olfactory segment of nasal mucosa, palpebral conjunctiva, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AQP5	3,079

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AQP5	P55064	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Passive transport by Aquaporins	1	878.5×	0.003	AQP5
Aquaporin-mediated transport	1	368.4×	0.004	AQP5
Transport of small molecules	1	25.1×	0.040	AQP5

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
pancreatic juice secretion	1	3370.4×	0.002	AQP5
saliva secretion	1	2106.5×	0.002	AQP5
cellular hypotonic response	1	1404.3×	0.002	AQP5
carbon dioxide transport	1	1296.3×	0.002	AQP5
water transport	1	991.3×	0.002	AQP5
camera-type eye morphogenesis	1	766.0×	0.002	AQP5
odontogenesis	1	526.6×	0.002	AQP5
protein homotetramerization	1	237.3×	0.004	AQP5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AQP5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AQP5	1	Binding:1

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	AQP5

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)
AQP5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.