obesity due to prohormone convertase I deficiency

Summary

obesity due to prohormone convertase I deficiency (MONDO:0010961) is a disease caused by PCSK1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PCSK1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 91
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001513	Obesity	Obligate (100%)
HP:0009126	Increased adipose tissue	Obligate (100%)
HP:0002591	Polyphagia	Very frequent (80-99%)
HP:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0002297	Red hair	Frequent (30-79%)
HP:0008915	Childhood-onset truncal obesity	Frequent (30-79%)
HP:0011734	Central adrenal insufficiency	Frequent (30-79%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002173	Hypoglycemic seizures	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0008213	Gonadotropin deficiency	Occasional (5-29%)
HP:0008245	Pituitary hypothyroidism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to prohormone convertase I deficiency
Mondo ID	MONDO:0010961
MeSH	C563423
OMIM	600955
Orphanet	71528
DOID	DOID:0111698
SNOMED CT	722053001
UMLS	C1833053
MedGen	318777
GARD	0016689
NORD	109523
Is cancer (heuristic)	no

Also known as: PCI deficiency · PCSK1 Deficiency

Data availability: 91 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › congenital hypogonadotropic hypogonadism › obesity due to prohormone convertase I deficiency

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Woodhouse-Sakati syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

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

91 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 12 pathogenic, 12 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14039	NM_000439.5(PCSK1):c.638_640del (p.Ala213del)	CAST	Pathogenic	no assertion criteria provided
14041	NM_000439.5(PCSK1):c.920C>T (p.Ser307Leu)	CAST	Pathogenic	no assertion criteria provided
1710315	NM_000439.5(PCSK1):c.595C>T (p.Arg199Ter)	CAST	Pathogenic	criteria provided, single submitter
1723151	NM_000439.5(PCSK1):c.1350_1353del (p.Val450_Asp451insTer)	CAST	Pathogenic	no assertion criteria provided
2661895	NM_000439.5(PCSK1):c.1024del (p.Trp342fs)	CAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255344	NM_000439.5(PCSK1):c.1213C>T (p.Arg405Ter)	CAST	Pathogenic	criteria provided, single submitter
14036	NM_000439.5(PCSK1):c.1447G>A (p.Gly483Arg)	LOC101929710	Pathogenic	no assertion criteria provided
14037	NM_000439.5(PCSK1):c.620+4A>C	LOC101929710	Pathogenic	no assertion criteria provided
14038	NM_000439.5(PCSK1):c.748G>T (p.Glu250Ter)	LOC101929710	Pathogenic	no assertion criteria provided
1710314	NM_000439.5(PCSK1):c.927C>G (p.Asn309Lys)	LOC101929710	Pathogenic	no assertion criteria provided
995956	NM_000439.5(PCSK1):c.238C>T (p.Arg80Ter)	LOC101929710	Pathogenic	no assertion criteria provided
1323428	NM_000439.5(PCSK1):c.958dup (p.Asp320fs)	PCSK1	Pathogenic	criteria provided, single submitter
1723149	NM_000439.5(PCSK1):c.1095+1G>T	PCSK1	Pathogenic	no assertion criteria provided
1339324	NM_000439.5(PCSK1):c.1313G>A (p.Arg438Gln)	CAST	Likely pathogenic	criteria provided, single submitter
1723150	NM_000439.5(PCSK1):c.1095+1G>A	CAST	Likely pathogenic	criteria provided, single submitter
3897763	NM_000439.5(PCSK1):c.1603C>T (p.Leu535Phe)	CAST	Likely pathogenic	criteria provided, single submitter
1333563	NM_000439.5(PCSK1):c.675C>A (p.Cys225Ter)	LOC101929710	Likely pathogenic	criteria provided, single submitter
2501705	NM_000439.5(PCSK1):c.818del (p.Asp273fs)	LOC101929710	Likely pathogenic	criteria provided, single submitter
807458	NM_000439.5(PCSK1):c.1688C>G (p.Pro563Arg)	LOC101929710	Likely pathogenic	criteria provided, single submitter
807459	NM_000439.5(PCSK1):c.1346T>C (p.Leu449Pro)	LOC101929710	Likely pathogenic	criteria provided, single submitter
1333251	NM_000439.5(PCSK1):c.1549C>T (p.Arg517Ter)	PCSK1	Likely pathogenic	criteria provided, single submitter
2203667	NM_000439.5(PCSK1):c.772C>A (p.Pro258Thr)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431898	NM_000439.5(PCSK1):c.1387G>A (p.Glu463Lys)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436278	NM_000439.5(PCSK1):c.1918A>G (p.Thr640Ala)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904570	NM_000439.5(PCSK1):c.1146G>A (p.Ser382=)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905357	NM_000439.5(PCSK1):c.1030G>A (p.Ala344Thr)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905360	NM_000439.5(PCSK1):c.927C>T (p.Asn309=)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906970	NM_000439.5(PCSK1):c.624C>T (p.His208=)	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907878	NM_000439.5(PCSK1):c.1884+13C>G	CAST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354650	NM_000439.5(PCSK1):c.709+11G>A	LOC101929710	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PCSK1	Definitive	Autosomal recessive	obesity due to prohormone convertase I deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCSK1	Orphanet:71528	Obesity due to prohormone convertase I deficiency
CAST	Orphanet:444138	Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCSK1	HGNC:8743	ENSG00000175426	P29120	Neuroendocrine convertase 1	gencc,clinvar
CAST	HGNC:1515	ENSG00000153113	P20810	Calpastatin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCSK1	Neuroendocrine convertase 1	Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues.
CAST	Calpastatin	Specific inhibition of calpain (calcium-dependent cysteine protease).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCSK1	Protease	yes	3.4.21.93	Peptidase_S8/S53_dom, P_dom, Galactose-bd-like_sf
CAST	Other/Unknown	no		Prot_inh_calpain, Calpastatin

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
postcentral gyrus	1
type B pancreatic cell	1
bronchial epithelial cell	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCSK1	197	broad	marker	type B pancreatic cell, islet of Langerhans, postcentral gyrus
CAST	301	tissue_specific	marker	calcaneal tendon, bronchial epithelial cell, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCSK1	2,641
CAST	1,152

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCSK1	P29120	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CAST	P20810	59.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Peptide hormone biosynthesis	1	713.8×	0.006	PCSK1
Incretin synthesis, secretion, and inactivation	1	519.1×	0.006	PCSK1
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	439.2×	0.006	PCSK1
Synthesis, secretion, and deacylation of Ghrelin	1	300.5×	0.006	PCSK1
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	259.6×	0.006	PCSK1
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.006	CAST
Insulin processing	1	228.4×	0.006	PCSK1
Peptide hormone metabolism	1	135.9×	0.009	PCSK1
Degradation of the extracellular matrix	1	58.9×	0.019	CAST
Metabolism of proteins	1	6.2×	0.155	PCSK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
presynaptic active zone organization	1	8426.0×	8e-04	CAST
peptide biosynthetic process	1	2106.5×	0.002	PCSK1
negative regulation of type B pancreatic cell apoptotic process	1	1053.2×	0.002	CAST
insulin processing	1	842.6×	0.002	PCSK1
peptide hormone processing	1	468.1×	0.003	PCSK1
cell-cell signaling	1	34.8×	0.033	PCSK1
proteolysis	1	17.1×	0.058	PCSK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCSK1	0	0
CAST	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PCSK1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCSK1	3.4.21.93	Proprotein convertase 1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	PCSK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CAST

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCSK1	2	—
CAST	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.