mal de Meleda

Summary

mal de Meleda (MONDO:0009552) is a disease caused by SLURP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLURP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001155	Abnormality of the hand	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0007404	Nonepidermolytic palmoplantar keratoderma	Very frequent (80-99%)
HP:0011123	Inflammatory abnormality of the skin	Very frequent (80-99%)
HP:0031190	Superficial dermal perivascular inflammatory infiltrate	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001218	Autoamputation	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0007390	Hyperkeratosis with erythema	Frequent (30-79%)
HP:0007447	Diffuse palmoplantar kyperkeratosis	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0025092	Epidermal acanthosis	Frequent (30-79%)
HP:0008064	Ichthyosis	Occasional (5-29%)
HP:0031452	Lichenoid skin lesion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mal de Meleda
Mondo ID	MONDO:0009552
OMIM	248300
Orphanet	87503
DOID	DOID:0060862
ICD-11	1850911834
SNOMED CT	239069005
UMLS	C0025221
MedGen	7522
GARD	0000092
NORD	1428
Is cancer (heuristic)	no

Also known as: keratosis palmoplantaris transgradiens of Siemens · keratosis palmoplantaris transgrediens of Siemens · mal de Meleda · MDM · Meleda Disease · Meleda disease

Data availability: 31 ClinVar variants · 6 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 › mal de Meleda

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, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, 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

31 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 12 pathogenic, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2504644	NM_020427.3(SLURP1):c.243C>A (p.Asp81Glu)	SLURP1	Pathogenic	no assertion criteria provided
3768003	P82S	SLURP1	Pathogenic	no assertion criteria provided
3768005	E60K	SLURP1	Pathogenic	no assertion criteria provided
3768006	C73del	SLURP1	Pathogenic	no assertion criteria provided
4599	NM_020427.3(SLURP1):c.82del (p.Cys28fs)	SLURP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4600	NM_020427.3(SLURP1):c.178+1G>A	SLURP1	Pathogenic	no assertion criteria provided
4601	NM_020427.3(SLURP1):c.286C>T (p.Arg96Ter)	SLURP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4602	NM_020427.3(SLURP1):c.256G>A (p.Gly86Arg)	SLURP1	Pathogenic	criteria provided, single submitter
4603	NM_020427.3(SLURP1):c.256G>C (p.Gly86Arg)	SLURP1	Pathogenic	no assertion criteria provided
4605	NM_020427.3(SLURP1):c.43T>C (p.Trp15Arg)	SLURP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4606	NM_020427.3(SLURP1):c.229T>C (p.Cys77Arg)	SLURP1	Pathogenic	no assertion criteria provided
4607	NM_020427.3(SLURP1):c.296G>A (p.Cys99Tyr)	SLURP1	Pathogenic	no assertion criteria provided
2446436	NM_020427.3(SLURP1):c.111C>A (p.Cys37Ter)	SLURP1	Likely pathogenic	criteria provided, single submitter
4604	NM_020427.3(SLURP1):c.1A>C (p.Met1Leu)	SLURP1	Likely pathogenic	criteria provided, single submitter
502120	NM_020427.3(SLURP1):c.310T>C (p.Ter104Arg)	SLURP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911883	NM_020427.3(SLURP1):c.167C>T (p.Thr56Met)	SLURP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500803	NM_020427.3(SLURP1):c.211C>T (p.Arg71Cys)	SLURP1	Uncertain significance	criteria provided, single submitter
362099	NM_020427.3(SLURP1):c.*14G>A	SLURP1	Uncertain significance	criteria provided, single submitter
362101	NM_020427.3(SLURP1):c.179-3C>T	SLURP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
362102	NM_020427.3(SLURP1):c.-7C>T	SLURP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3768004	NM_020427.3(SLURP1):c.280T>A (p.Cys94Ser)	SLURP1	Uncertain significance	criteria provided, single submitter
77205	NM_020427.3(SLURP1):c.10C>T (p.Arg4Cys)	SLURP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
908937	NM_020427.3(SLURP1):c.158C>T (p.Thr53Met)	SLURP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
908938	NM_020427.3(SLURP1):c.141C>T (p.Asp47=)	SLURP1	Uncertain significance	criteria provided, single submitter
908939	NM_020427.3(SLURP1):c.125G>A (p.Arg42His)	SLURP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
908940	NM_020427.3(SLURP1):c.47G>T (p.Ser16Ile)	SLURP1	Uncertain significance	criteria provided, single submitter
910652	NM_020427.3(SLURP1):c.*146G>A	SLURP1	Uncertain significance	criteria provided, single submitter
911881	NM_020427.3(SLURP1):c.*10G>A	SLURP1	Uncertain significance	criteria provided, single submitter
911882	NM_020427.3(SLURP1):c.202G>A (p.Val68Met)	SLURP1	Uncertain significance	criteria provided, single submitter
362098	NM_020427.3(SLURP1):c.*143G>A	SLURP1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
SLURP1	Strong	Autosomal recessive	mal de Meleda	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLURP1	Orphanet:87503	Mal de Meleda

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
SLURP1	HGNC:18746	ENSG00000126233	P55000	Secreted Ly-6/uPAR-related protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLURP1	Secreted Ly-6/uPAR-related protein 1	Has an antitumor activity.

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)
SLURP1	Other/Unknown	no		LY6_UPA_recep-like, Snake_toxin-like_sf, Ly-6/neurotoxin-like_GPI-ap

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
esophagus mucosa	1
lower esophagus mucosa	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLURP1	155	tissue_specific	marker	lower esophagus mucosa, skin of leg, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLURP1	749

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLURP1	P55000	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
urokinase plasminogen activator signaling pathway	1	4213.0×	0.002	SLURP1
cell activation	1	1685.2×	0.002	SLURP1
neuromuscular process controlling posture	1	1053.2×	0.003	SLURP1
negative regulation of keratinocyte proliferation	1	702.2×	0.003	SLURP1
locomotory behavior	1	179.3×	0.009	SLURP1
negative regulation of cell migration	1	111.6×	0.012	SLURP1
negative regulation of cell population proliferation	1	42.1×	0.027	SLURP1
cell adhesion	1	37.5×	0.027	SLURP1

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
SLURP1	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	SLURP1

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)
SLURP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.