Hyperzincemia with functional zinc depletion

Summary

Hyperzincemia with functional zinc depletion (MONDO:0011174) is a disease caused by PSTPIP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PSTPIP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperzincemia with functional zinc depletion
Mondo ID	MONDO:0011174
MeSH	C566595
OMIM	601979
Orphanet	251523
DOID	DOID:0061185
UMLS	C4760957
MedGen	1813911
GARD	0027262
Is cancer (heuristic)	no

Also known as: hyperzincemia and hypercalprotectinemia · hyperzincemia with functional zinc depletion · recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndrome

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › disorder of metabolite absorption and transport › disorder of mineral absorption and transport › disorder of zinc metabolism › hyperzincemia with functional zinc depletion

Related subtypes (2): acrodermatitis enteropathica, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy 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

6 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3340543	NM_003978.5(PSTPIP1):c.769G>A (p.Glu257Lys)	PSTPIP1	Pathogenic	no assertion criteria provided
97810	NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)	PSTPIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3381185	NM_003978.5(PSTPIP1):c.244C>T (p.Gln82Ter)	PSTPIP1	Uncertain significance	criteria provided, single submitter
3892204	NM_003978.5(PSTPIP1):c.-65G>A	PSTPIP1	Uncertain significance	criteria provided, single submitter
4293063	NM_003978.5(PSTPIP1):c.1148G>A (p.Gly383Glu)	PSTPIP1	Uncertain significance	criteria provided, single submitter
581741	NM_003978.5(PSTPIP1):c.503A>G (p.Lys168Arg)	PSTPIP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
PSTPIP1	Strong	Autosomal dominant	hyperzincemia with functional zinc depletion	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSTPIP1	Orphanet:251523	Hyperzincemia and hypercalprotectinemia
PSTPIP1	Orphanet:69126	PAPA syndrome

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
PSTPIP1	HGNC:9580	ENSG00000140368	O43586	Proline-serine-threonine phosphatase-interacting protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSTPIP1	Proline-serine-threonine phosphatase-interacting protein 1	Involved in regulation of the actin cytoskeleton.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSTPIP1	Scaffold/PPI	no		FCH_dom, SH3_domain, AH/BAR_dom_sf

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
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSTPIP1	179	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSTPIP1	2,508

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSTPIP1	O43586	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
The NLRP3 inflammasome	1	671.8×	0.002	PSTPIP1
Purinergic signaling in leishmaniasis infection	1	423.0×	0.002	PSTPIP1

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
endocytosis	1	95.2×	0.037	PSTPIP1
inflammatory response	1	37.7×	0.037	PSTPIP1
cell adhesion	1	37.5×	0.037	PSTPIP1
innate immune response	1	33.6×	0.037	PSTPIP1
signal transduction	1	16.1×	0.062	PSTPIP1

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
PSTPIP1	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	PSTPIP1

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)
PSTPIP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.