NRL

protein-coding

neural retina leucine zipper, the group of Basic leucine zipper proteins

Gene summary

This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001354768.3

Inheritance

AR, AD

ClinVar variants

P:44U:143B:50

Top phenotype

Retinitis pigmentosa 27; Clumped pigmentary retinal degeneration

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr14:24,078,662-24,115,010

External References & Databases

Ensembl (ENSG00000129535)

Transcript & Mutation Effects

hg38 • Region Span ~36.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 27DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013402

Submitter: G2P

retinitis pigmentosa 27DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013402

Submitter: ClinGen

*NRL* was first reported in relation to *NRL*-related dominant retinopathy in 1999 (Bessant et al., PMID: 10192380). In 2004, loss of function variants were linked to a recessive form of retinopathy (Nishiguchi et al., PMID: 15591106 ). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Retinitis pigmentosa 27 (OMIM:613750) as *NRL*-related dominant retinopathy and *NRL*-related recessive retinopathy (also called clumped pigmentary retinal degeneration or enhanced S-cone syndrome). The split curation for NRL-related recessive retinopathy has been curated separately. Nine missense variants that have been reported in 14 probands in 10 publications (PMIDs: 10192380, 11039579, 11385710, 11879142, 15994872, 21981118, 27081294, 28106895, 31736247, 35653045) are included in this curation, including segregation analysis in three families. The mechanism of pathogenicity appears to be gain of function in which the altered NRL protein over activates the rhodopsin promoter. This gene-disease relationship is also supported by expression studies and* in vitro* functional assays (PMIDs: 1147710816505381, 17335001, 8552602). These studies show that NRL is specifically expressed in rod photoreceptors and is capable of activating the rhodopsin promoter. The pathogenic variants alter phosphorylation of NRL and result in increased activation of the rhodopsin promoter. In summary, there is definitive evidence supporting the relationship between *NRL* and *NRL*-related dominant retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on the meeting date March, 6, 2025] (SOP Version 11)].

enhanced S-cone syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: Ambry Genetics

retinitis pigmentosa 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013402

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013402

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013402

Submitter: PanelApp Australia

retinitis pigmentosa 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013402

Submitter: PanelApp Australia

retinitis pigmentosa 27DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013402

Submitter: G2P

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

retinitis pigmentosa 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013402

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Retinitis pigmentosa 27; Clumped pigmentary retinal degenerationAD/AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 10192380; 11039579; 12796249; 15591106; 17335001

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NRL variants in ClinVar

21 Conditions Cataloged

not providedTotal: 459

not specifiedTotal: 135

Inborn genetic diseasesTotal: 34

PCK2-related disorderTotal: 29

NRL-related disorderTotal: 28

NRL-related disordersTotal: 20

Retinitis pigmentosa 27Total: 18

Retinitis pigmentosaTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001354768.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	4 clinvar	47 clinvar		52
missense	2 clinvar	14 clinvar	134 clinvar	3 clinvar		153
nonsense	2 clinvar	5 clinvar	1 clinvar			8
start loss						0
frameshift	10 clinvar	7 clinvar	4 clinvar			21
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	15	29	143	50	0	237

Highest pathogenic variant AF is 0.00011016958

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001354768.3	RefSeq	NP_001341697.1	2	MANE Select
ENST00000561028.6	Ensembl	ENSP00000454062.2	2	MANE Select
NM_001354769.1	RefSeq	NP_001341698.1	2	Standard
NM_001354770.2	RefSeq	NP_001341699.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tacrolimus/Cyclosporine Pathway, Pharmacodynamics

Biological Process

transcription by RNA polymerase II
regulation of rhodopsin gene expression
visual perception
positive regulation of rhodopsin gene expression
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000561028
Coding exons: 2
Length: 34908
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125743
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.614	103	122	0.844	0.00000601	1457
Missense (PolyPhen)		30	42.349	0.70841		554
Synonymous	-0.776	63	55.6	1.13	0.00000269	548
Loss of Function	1.41	3	7.03	0.427	3.87e-7	77

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B (PubMed:21981118). Functions also as a transcriptional coactivator, stimulating transcription mediated by the transcription factor CRX and NR2E3 (PubMed:17335001). Binds in a sequence-specific manner to the rhodopsin promoter (PubMed:17335001). {ECO:0000269|PubMed:17335001, ECO:0000269|PubMed:21981118}.;
Disease: DISEASE: Retinitis pigmentosa 27 (RP27) [MIM:613750]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:10192380, ECO:0000269|PubMed:11385710, ECO:0000269|PubMed:11879142, ECO:0000269|PubMed:15591106, ECO:0000269|PubMed:15994872, ECO:0000269|PubMed:17335001, ECO:0000269|PubMed:21981118, ECO:0000269|PubMed:22334370}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinal degeneration autosomal recessive clumped pigment type (RDCP) [MIM:613750]: A retinopathy characterized by night blindness since early childhood, consistent with a severe reduction in rod function. Color vision is normal although there is a relatively enhanced function of short-wavelength-sensitive cones in the macula. Signs of retinal degeneration and clusters of clumped pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium are present. {ECO:0000269|PubMed:15591106, ECO:0000269|PubMed:17335001}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.422

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium