Purine nucleoside phosphorylase deficiency

Summary

Purine nucleoside phosphorylase deficiency (MONDO:0013171) is a disease caused by PNP (GenCC Strong), with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include mycophenolate mofetil.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: PNP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 276
• Phenotypes (HPO): 29
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		72	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0002843	Abnormal T cell morphology	Very frequent (80-99%)
HP:0011935	Decreased urinary urate	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0003537	Hypouricemia	Frequent (30-79%)
HP:0004430	Severe combined immunodeficiency	Frequent (30-79%)
HP:0005363	Humoral immunodeficiency	Frequent (30-79%)
HP:0032166	Unusual gastrointestinal infection	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001888	Lymphopenia	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0011442	Abnormality of central motor function	Occasional (5-29%)
HP:0045080	Decreased proportion of CD3-positive T cells	Occasional (5-29%)
HP:0100021	Cerebral palsy	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001973	Autoimmune thrombocytopenia	Very rare (<1-4%)
HP:0002725	Systemic lupus erythematosus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	purine nucleoside phosphorylase deficiency
Mondo ID	MONDO:0013171
MeSH	C562587
OMIM	613179
Orphanet	760
DOID	DOID:5813
NCIT	C176817, C3963
SNOMED CT	60743005
UMLS	C0268125
MedGen	75653
GARD	0004606
Is cancer (heuristic)	no

Also known as: immunodeficiency due to purine nucleoside phosphorylase deficiency · PNP deficiency · PNPase deficiency · purine nucleoside phosphorylase deficiency · purine-nucleoside phosphorylase deficiency

Data availability: 276 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of purine or pyrimidine metabolism › inborn disorder of purine metabolism › purine nucleoside phosphorylase deficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, adenylosuccinate lyase deficiency, familial juvenile hyperuricemic nephropathy type 1, mitochondrial DNA depletion syndrome 3 (hepatocerebral type), phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive 5, AICA-ribosiduria, adenosine monophosphate deaminase deficiency, adenine phosphoribosyltransferase deficiency, developmental and epileptic encephalopathy, 35, hypoxanthine-guanine phosphoribosyltransferase deficiency, hereditary xanthinuria, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, hemolytic anemia due to erythrocyte adenosine deaminase overproduction, PAICS deficiency

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

276 retrieved; paginated sample, class counts are floors:

102 likely benign, 100 uncertain significance, 28 benign, 21 pathogenic, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2422759	NC_000014.8:g.(?20915399)(22005055_?)del	OR6S1	Pathogenic	criteria provided, single submitter
1071551	NM_000270.4(PNP):c.171_172delinsTT (p.Arg58Ter)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1074418	NM_000270.4(PNP):c.547dup (p.Glu183fs)	PNP	Pathogenic	criteria provided, single submitter
1076064	NM_000270.4(PNP):c.244C>T (p.Gln82Ter)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1324943	NM_000270.4(PNP):c.12-1G>C	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344922	NM_000270.4(PNP):c.199C>T (p.Arg67Ter)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13988	NM_000270.4(PNP):c.265G>A (p.Glu89Lys)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13990	NM_000270.4(PNP):c.383A>G (p.Asp128Gly)	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13991	NM_000270.4(PNP):c.701G>C (p.Arg234Pro)	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13994	NM_000270.4(PNP):c.731del (p.Lys244fs)	PNP	Pathogenic	no assertion criteria provided
13995	NM_000270.4(PNP):c.70C>T (p.Arg24Ter)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13996	NM_000270.4(PNP):c.172C>T (p.Arg58Ter)	PNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13997	NM_000270.4(PNP):c.285+1G>A	PNP	Pathogenic	no assertion criteria provided
1458553	NM_000270.4(PNP):c.700C>T (p.Arg234Ter)	PNP	Pathogenic	criteria provided, single submitter
1804667	NM_000270.4(PNP):c.601G>T (p.Glu201Ter)	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2163413	NM_000270.4(PNP):c.406dup (p.Ile136fs)	PNP	Pathogenic	criteria provided, single submitter
2736067	NM_000270.4(PNP):c.569G>T (p.Gly190Val)	PNP	Pathogenic	criteria provided, single submitter
2844130	NM_000270.4(PNP):c.632_644dup (p.Asp215fs)	PNP	Pathogenic	criteria provided, single submitter
3023072	NM_000270.4(PNP):c.513del (p.Arg171fs)	PNP	Pathogenic	criteria provided, single submitter
4710887	NM_000270.4(PNP):c.694G>T (p.Gly232Ter)	PNP	Pathogenic	criteria provided, single submitter
4712212	NM_000270.4(PNP):c.397del (p.Arg133fs)	PNP	Pathogenic	criteria provided, single submitter
4717066	NM_000270.4(PNP):c.519_522dup (p.Leu175fs)	PNP	Pathogenic	criteria provided, single submitter
4731735	NM_000270.4(PNP):c.472del (p.Arg158fs)	PNP	Pathogenic	criteria provided, single submitter
4731810	NM_000270.4(PNP):c.281G>A (p.Trp94Ter)	PNP	Pathogenic	criteria provided, single submitter
505116	NM_000270.4(PNP):c.286-18G>A	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636509	NM_000270.4(PNP):c.769C>G (p.His257Asp)	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636518	NM_000270.4(PNP):c.437C>T (p.Pro146Leu)	PNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
845655	NM_000270.4(PNP):c.751del (p.Ser251fs)	PNP	Pathogenic	criteria provided, single submitter
13989	NM_000270.4(PNP):c.520G>C (p.Ala174Pro)	PNP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137547	NM_000270.4(PNP):c.387_389del (p.Ile129del)	PNP	Likely pathogenic	criteria provided, single submitter

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
PNP	Strong	Autosomal recessive	purine nucleoside phosphorylase deficiency	3
PPY	Strong	Autosomal recessive	purine nucleoside phosphorylase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNP	Orphanet:760	Purine nucleoside phosphorylase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PNP	HGNC:7892	ENSG00000198805	P00491	Purine nucleoside phosphorylase	gencc,clinvar
PPY	HGNC:9327	ENSG00000108849	P01298	Pancreatic polypeptide prohormone	gencc,clinvar
OR6S1	HGNC:15363	ENSG00000181803	Q8NH40	Olfactory receptor 6S1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNP	Purine nucleoside phosphorylase	Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
PPY	Pancreatic polypeptide prohormone	Hormone secreted by pancreatic cells that acts as a regulator of pancreatic and gastrointestinal functions probably by signaling through the G protein-coupled receptor NPY4R2.
OR6S1	Olfactory receptor 6S1	Odorant receptor.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
GPCR	1	8.0×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNP	Enzyme (other)	yes	2.4.2.1	Nucleoside_phosphorylase_d, Purine_phosphorylase, Pur_Nuc_Pase_Ino/Guo-sp
PPY	Other/Unknown	no		Pancreatic_hormone-like, Pancreatic_hormone-like_CS
OR6S1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM

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)	1
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
monocyte	1
mucosa of transverse colon	1
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
type B pancreatic cell	1
bone marrow cell	1
colonic epithelium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNP	255	ubiquitous	marker	corpus epididymis, mucosa of transverse colon, monocyte
PPY	85	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, male germ line stem cell (sensu Vertebrata) in testis
OR6S1	2		yes	bone marrow cell, colonic epithelium, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPY	2,107
PNP	1,943
OR6S1	105

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PNP	P00491	41
PPY	P01298	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR6S1	Q8NH40	86.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective PNP disrupts phosphorolysis of (deoxy)guanosine and (deoxy)inosine	1	3806.7×	0.002	PNP
Purine catabolism	1	346.1×	0.007	PNP
Ribavirin ADME	1	346.1×	0.007	PNP
Purine salvage	1	292.8×	0.007	PNP
Peptide ligand-binding receptors	1	24.7×	0.064	PPY
G alpha (i) signalling events	1	13.0×	0.100	PPY
Expression and translocation of olfactory receptors	1	9.4×	0.118	OR6S1
Neutrophil degranulation	1	7.7×	0.124	PNP

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
nicotinamide riboside catabolic process	1	8426.0×	9e-04	PNP
inosine catabolic process	1	4213.0×	9e-04	PNP
deoxyinosine catabolic process	1	4213.0×	9e-04	PNP
urate biosynthetic process	1	4213.0×	9e-04	PNP
purine-containing compound salvage	1	4213.0×	9e-04	PNP
deoxyadenosine catabolic process	1	2808.7×	0.001	PNP
dAMP catabolic process	1	2106.5×	0.001	PNP
IMP catabolic process	1	1685.2×	0.001	PNP
nucleotide biosynthetic process	1	1685.2×	0.001	PNP
purine ribonucleoside salvage	1	1203.7×	0.002	PNP
allantoin metabolic process	1	936.2×	0.002	PNP
positive regulation of alpha-beta T cell differentiation	1	842.6×	0.002	PNP
feeding behavior	1	271.8×	0.005	PPY
nucleobase-containing compound metabolic process	1	263.3×	0.005	PNP
positive regulation of interleukin-2 production	1	234.1×	0.006	PNP
protein secretion	1	131.7×	0.009	PPY
positive regulation of T cell proliferation	1	129.6×	0.009	PNP
neuropeptide signaling pathway	1	86.0×	0.013	PPY
response to xenobiotic stimulus	1	34.5×	0.030	PNP
immune response	1	23.5×	0.042	PNP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PNP	CLADRIBINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PNP	9	4
PPY	0	0
OR6S1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLADRIBINE	4	PNP
ACYCLOVIR	4	PNP
FORODESINE	4	PNP
FORODESINE HYDROCHLORIDE	4	PNP
GUANINE	3	PNP
GALIDESIVIR	2	PNP
ULODESINE	2	PNP
PELDESINE	2	PNP
DEZAGUANINE	2	PNP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PNP	156	Binding:139, Functional:16, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNP	2.4.2.1	purine-nucleoside phosphorylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PNP	156

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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.

Compound	Max phase	Cohort target (bioactivity)
CLADRIBINE	4	PNP
ACYCLOVIR	4	PNP
FORODESINE	4	PNP
FORODESINE HYDROCHLORIDE	4	PNP
GUANINE	3	PNP
GALIDESIVIR	2	PNP
ULODESINE	2	PNP
PELDESINE	2	PNP
DEZAGUANINE	2	PNP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PNP
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	OR6S1
E	Difficult family or no structure, no drug	1	PPY

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)
PPY	0	—
OR6S1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MYCOPHENOLATE MOFETIL	4	1