Retinitis pigmentosa 27

Summary

Retinitis pigmentosa 27 (MONDO:0013402) is a disease caused by NRL (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NRL (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	retinitis pigmentosa 27
Mondo ID	MONDO:0013402
MeSH	C563526
OMIM	613750
DOID	DOID:0110397
UMLS	C1834329
MedGen	320323
GARD	0015700
Is cancer (heuristic)	no

Also known as: NRL retinitis pigmentosa · retinitis pigmentosa 27 · retinitis pigmentosa caused by mutation in NRL · retinitis pigmentosa type 27 · RP27

Data availability: 17 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › retinitis pigmentosa › retinitis pigmentosa 27

Related subtypes (101): retinitis pigmentosa 6, cone-rod dystrophy 2, retinitis pigmentosa 1, retinitis pigmentosa 9, retinitis pigmentosa 10, dominant pericentral pigmentary retinopathy, late-adult onset retinitis pigmentosa, autosomal recessive pericentral pigmentary retinopathy, retinitis pigmentosa 3, retinitis pigmentosa 24, retinitis pigmentosa 23, retinitis pigmentosa 34, retinitis pigmentosa 2, retinitis pigmentosa Y-linked, retinitis pigmentosa 13, retinitis pigmentosa 12, retinitis pigmentosa 14, retinitis pigmentosa 11, retinitis pigmentosa 17, retinitis pigmentosa 18, retinitis pigmentosa 19, retinitis pigmentosa 22, retinitis pigmentosa 25, retinitis pigmentosa 28, retinitis pigmentosa 30, retinitis pigmentosa 7, retinitis pigmentosa 26, retinitis pigmentosa 32, retinitis pigmentosa 31, retinitis pigmentosa 35, retinitis pigmentosa 33, retinitis pigmentosa 36, retinitis pigmentosa 37, retinitis pigmentosa 41, retinitis pigmentosa 29, retinitis pigmentosa 46, retinitis pigmentosa 42, retinitis pigmentosa 50, retinitis pigmentosa 54, retinitis pigmentosa 51, retinitis pigmentosa 55, retinitis pigmentosa 56, retinitis pigmentosa 57, retinitis pigmentosa 58, cone-rod dystrophy 15, retinitis pigmentosa 4, retinitis pigmentosa 49, retinitis pigmentosa 47, retinitis pigmentosa 45, retinitis pigmentosa 44, retinitis pigmentosa 20, retinitis pigmentosa 40, retinitis pigmentosa 39, retinitis pigmentosa 43, retinitis pigmentosa 48, retinitis pigmentosa 59, retinitis pigmentosa 38, retinitis pigmentosa 60, retinitis pigmentosa 61, retinitis pigmentosa 62, retinitis pigmentosa 63, cone-rod dystrophy 16, retinitis pigmentosa 66, retinitis pigmentosa with or without situs inversus, retinitis pigmentosa 67, retinitis pigmentosa 68, retinitis pigmentosa 69, retinitis pigmentosa 70, retinal dystrophy and obesity, retinitis pigmentosa 71, retinitis pigmentosa 72, retinitis pigmentosa 73, retinitis pigmentosa 74, retinitis pigmentosa 75, retinitis pigmentosa 76, retinitis pigmentosa 77, retinitis pigmentosa 92, retinitis pigmentosa 93, retinitis pigmentosa 83, retinitis pigmentosa 84, retinitis pigmentosa 85, retinitis pigmentosa 86, retinitis pigmentosa 87 with choroidal involvement, retinitis pigmentosa 88, retinitis pigmentosa 90, retinitis pigmentosa 81, retinitis pigmentosa 78, retinitis pigmentosa 79, retinitis pigmentosa 80, retinitis pigmentosa 94, variable age at onset, retinitis pigmentosa 53, retinitis pigmentosa 65, retinitis pigmentosa 64, retinitis pigmentosa 95, retinitis pigmentosa 96, retinitis pigmentosa 97, retinitis pigmentosa 98, retinitis pigmentosa 99, retinitis pigmentosa 100, retinitis pigmentosa 101, retinitis pigmentosa 7, digenic

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

17 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
14042	NM_001354768.3(NRL):c.148T>A (p.Ser50Thr)	NRL	Pathogenic	no assertion criteria provided
14043	NM_001354768.3(NRL):c.223dup (p.Leu75fs)	NRL	Pathogenic	criteria provided, multiple submitters, no conflicts
195258	NM_001354768.3(NRL):c.151C>T (p.Pro51Ser)	NRL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
369652	NM_001354768.3(NRL):c.91C>T (p.Arg31Ter)	NRL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560472	NM_001354768.3(NRL):c.104dup (p.Thr36fs)	NRL	Pathogenic	no assertion criteria provided
623368	NM_001354768.3(NRL):c.339C>G (p.Tyr113Ter)	NRL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
916413	NM_001354768.3(NRL):c.152C>T (p.Pro51Leu)	NRL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329503	NM_001354768.3(NRL):c.619C>T (p.Arg207Cys)	LOC130055387	Likely pathogenic	criteria provided, single submitter
3767337	NM_001354768.3(NRL):c.152C>G (p.Pro51Arg)	NRL	Likely pathogenic	criteria provided, single submitter
3780043	NM_001354768.3(NRL):c.22del (p.Leu8fs)	NRL	Likely pathogenic	criteria provided, single submitter
4291979	NM_001354768.3(NRL):c.147_149del (p.Ser50del)	NRL	Likely pathogenic	criteria provided, single submitter
853152	NM_001354768.3(NRL):c.654del (p.Cys219fs)	LOC130055387	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1065724	NM_001354768.3(NRL):c.152C>A (p.Pro51His)	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451808	NM_004563.4(PCK2):c.577C>T (p.Arg193Ter)	PCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065586	NM_001354768.3(NRL):c.-27-11564C>T	NRL	Uncertain significance	criteria provided, single submitter
39510	NM_001354768.3(NRL):c.287T>C (p.Met96Thr)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
882488	NM_001354768.3(NRL):c.407C>T (p.Ala136Val)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
NRL	Definitive	Autosomal dominant	retinitis pigmentosa 27	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NRL	Orphanet:791	Retinitis pigmentosa
PCK2	Orphanet:2880	Phosphoenolpyruvate carboxykinase deficiency

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
NRL	HGNC:8002	ENSG00000129535	P54845	Neural retina-specific leucine zipper protein	gencc,clinvar
PCK2	HGNC:8725	ENSG00000100889	Q16822	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NRL	Neural retina-specific leucine zipper protein	Acts as a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B.
PCK2	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial	Mitochondrial phosphoenolpyruvate carboxykinase that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors deriv…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NRL	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf
PCK2	Kinase	yes	4.1.1.32	PEP_carboxykinase_GTP, PEP_carboxykinase_N, PEP_carboxykinase_C

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
cortical plate	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
right lobe of liver	1
small intestine Peyer’s patch	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NRL	129	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, cortical plate
PCK2	172	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, small intestine Peyer’s patch

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCK2	2,290
NRL	937

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCK2	Q16822	94.04
NRL	P54845	72.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Gluconeogenesis	1	439.2×	0.002	PCK2

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
propionate catabolic process	1	4213.0×	0.002	PCK2
obsolete glycerol biosynthetic process from pyruvate	1	4213.0×	0.002	PCK2
pyruvate biosynthetic process	1	1053.2×	0.004	PCK2
retinal rod cell development	1	842.6×	0.004	NRL
oxaloacetate metabolic process	1	766.0×	0.004	PCK2
positive regulation of ferroptosis	1	766.0×	0.004	PCK2
hepatocyte differentiation	1	601.9×	0.005	PCK2
cellular response to dexamethasone stimulus	1	290.6×	0.008	PCK2
response to starvation	1	234.1×	0.009	PCK2
gluconeogenesis	1	162.0×	0.012	PCK2
cellular response to glucose stimulus	1	133.8×	0.012	PCK2
positive regulation of insulin secretion	1	127.7×	0.012	PCK2
cellular response to insulin stimulus	1	85.1×	0.017	PCK2
cellular response to tumor necrosis factor	1	81.8×	0.017	PCK2
response to lipopolysaccharide	1	62.4×	0.020	PCK2
visual perception	1	39.8×	0.030	NRL
positive regulation of gene expression	1	19.4×	0.057	NRL
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	NRL
regulation of transcription by RNA polymerase II	1	5.8×	0.164	NRL

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
NRL	0	0
PCK2	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
PCK2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCK2	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)

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	0
D	Druggable family + AlphaFold only, no drug	1	PCK2
E	Difficult family or no structure, no drug	1	NRL

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)
NRL	0	—
PCK2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.