NXNL1

Summary

NXNL1 (nucleoredoxin like 1, HGNC:25179) is a protein-coding gene on chromosome 19p13.11, encoding Nucleoredoxin-like protein 1 (Q96CM4). Thioredoxin-like protein that protects retinal rod and cone photoreceptors against oxidative stress and photo-oxidative damage.

Retinitis pigmentosa (RP) is a disease that leads to blindness by degeneration of cone photoreceptors. Rods produce factors required for cone viability. The protein encoded by this gene is one of those factors and is similar to a truncated form of thioredoxin. This gene has been proposed to have therapeutic value against RP.

Source: NCBI Gene 115861 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leber congenital amaurosis (Limited, GenCC)
• Clinical variants (ClinVar): 56 total
• MANE Select transcript: NM_138454

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25179
Approved symbol	NXNL1
Name	nucleoredoxin like 1
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	RDCVF
Ensembl gene	ENSG00000171773
Ensembl biotype	protein_coding
OMIM	608791
Entrez	115861

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000301944

RefSeq mRNA: 1 — MANE Select: NM_138454 NM_138454

CCDS: CCDS12360

Canonical transcript exons

ENST00000301944 — 2 exons

Exon	Start	End
ENSE00001128044	17460544	17460926
ENSE00001255300	17455425	17455959

Expression profiles

Bgee: expression breadth broad, 92 present calls, max score 78.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1628 / max 67.3721, expressed in 11 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179872	0.1059	9
179870	0.0269	7
179869	0.0161	8
179871	0.0138	7

Top tissues by expression

120 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.31	silver quality
right adrenal gland cortex	UBERON:0035827	68.52	gold quality
left adrenal gland cortex	UBERON:0035825	65.82	gold quality
right adrenal gland	UBERON:0001233	65.70	gold quality
apex of heart	UBERON:0002098	64.96	gold quality
left adrenal gland	UBERON:0001234	64.59	gold quality
subcutaneous adipose tissue	UBERON:0002190	60.08	gold quality
adrenal gland	UBERON:0002369	60.06	gold quality
adipose tissue	UBERON:0001013	59.38	gold quality
omental fat pad	UBERON:0010414	58.71	gold quality
putamen	UBERON:0001874	53.70	gold quality
substantia nigra	UBERON:0002038	52.52	gold quality
thoracic mammary gland	UBERON:0005200	51.15	gold quality
heart left ventricle	UBERON:0002084	50.96	gold quality
right atrium auricular region	UBERON:0006631	49.93	gold quality
caudate nucleus	UBERON:0001873	49.44	gold quality
left ovary	UBERON:0002119	48.81	gold quality
anterior cingulate cortex	UBERON:0009835	48.36	gold quality
Ammon’s horn	UBERON:0001954	48.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	47.81	gold quality
right ovary	UBERON:0002118	47.79	gold quality
ovary	UBERON:0000992	47.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	47.50	gold quality
heart	UBERON:0000948	47.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	46.86	gold quality
gastrocnemius	UBERON:0001388	46.59	gold quality
temporal lobe	UBERON:0001871	46.23	gold quality
right uterine tube	UBERON:0001302	46.12	silver quality
amygdala	UBERON:0001876	45.97	gold quality
right frontal lobe	UBERON:0002810	45.82	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX4, SP3, VSX1, VSX2, ZNF91

miRNA regulators (miRDB)

9 targeting NXNL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4639-3P	97.54	67.12	787

Literature-anchored findings (GeneRIF, showing 7)

• is a truncated thioredoxin-like protein specifically expressed by photoreceptors. The identification of this protein offers new treatment possibilities for retinitis pigmentosa (PMID:15220920)
• RdCVF variants have roles in leber congenital amaurosis (PMID:17249548)
• TXNL6 probably protects retinal cells from photooxidative damage-induced apoptosis via upregulation of NF-kappaB activity (PMID:18474255)
• CHX10 regulates RdCVF promoter activity in the inner retina. (PMID:19843539)
• regulation of the Nucleoredoxin-like genes involves a CRX responsive element that can act as both as a positive regulator of promoter activity and as a modulator of cell-type specificity (PMID:20949100)
• Data suggest a critical role for TXNL6 in MsrA repair of essential lens proteins under oxidative stress conditions and that TXNL6 is important for MsrA defense protection against cataract. (PMID:21079812)
• Study shows that RdCVF acts through binding to Basigin-1 (BSG1), a transmembrane protein expressed specifically by photoreceptors. BSG1 binds to the glucose transporter GLUT1, resulting in increased glucose entry into cones. (PMID:25957687)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nxnl1	ENSDARG00000052035
mus_musculus	Nxnl1	ENSMUSG00000034829
rattus_norvegicus	Nxnl1	ENSRNOG00000042658
caenorhabditis_elegans		WBGENE00011038
caenorhabditis_elegans		WBGENE00019717

Paralogs (2): NXNL2 (ENSG00000130045), NXN (ENSG00000167693)

Protein

Protein identifiers

Nucleoredoxin-like protein 1 — Q96CM4 (reviewed: Q96CM4)

Alternative names: Rod-derived cone viability factor, Thioredoxin-like protein 6

All UniProt accessions (1): Q96CM4

UniProt curated annotations — full annotation on UniProt →

Function. Thioredoxin-like protein that protects retinal rod and cone photoreceptors against oxidative stress and photo-oxidative damage. Plays a role in the inhibition of TAU phosphorylation and protects TAU against oxidative stress in the retina. Acts as a reducing system for MSRA, facilitating the repair of oxidized proteins such as alpha-crystallin (CRYAA/CRYAB) and cytochrome c (CYCS) in the lens during oxidative stress conditions. Plays an important role in retinal cone photoreceptor survival. In association with glucose transporter SLC16A1/GLUT1 and BSG, promotes retinal cone survival by enhancing aerobic glycolysis and accelerating the entry of glucose into photoreceptors. May play a role in cone cell viability, slowing down cone degeneration, does not seem to play a role in degenerating rods.

Subunit / interactions. Interacts with isoform 1 of BSG.

Subcellular location. Cytoplasm. Mitochondrion Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Expressed in the lens epithelium and fiber cells (at protein level). Expressed in the retina, stomach, kidney, heart, colon, and spleen.

Induction. By oxidative stress (at protein level).

Similarity. Belongs to the nucleoredoxin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96CM4-1	1, Long	yes
Q96CM4-2	2, Short

RefSeq proteins (1): NP_612463* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012336	Thioredoxin-like_fold	Domain
IPR013766	Thioredoxin_domain	Domain
IPR029520	RdCVF	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF13905

UniProt features (12 total): sequence variant 7, chain 1, domain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96CM4-F1	74.82	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 35 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_CELL_REDOX_HOMEOSTASIS, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOCC_NEURON_PROJECTION, GOBP_RETINA_HOMEOSTASIS, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_HOMEOSTATIC_PROCESS, chr19p13, GOCC_CILIUM, GOCC_PHOTORECEPTOR_OUTER_SEGMENT, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, MIKKELSEN_ES_LCP_WITH_H3K4ME3, GOCC_NON_MOTILE_CILIUM, GOCC_9PLUS0_NON_MOTILE_CILIUM

GO Biological Process (5): response to oxidative stress (GO:0006979), cell redox homeostasis (GO:0045454), photoreceptor cell maintenance (GO:0045494), response to photooxidative stress (GO:0080183), signal transduction (GO:0007165)

GO Molecular Function (2): receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (4): photoreceptor outer segment (GO:0001750), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to stress	1
cellular homeostasis	1
retina homeostasis	1
multicellular organismal process	1
response to oxidative stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
binding	1
photoreceptor cell cilium	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

609 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NXNL1	VSX1	Q9NZR4	841
NXNL1	PDE6B	P35913	832
NXNL1	VSX2	P58304	813
NXNL1	PAX4	O43316	753
NXNL1	TXN	P10599	752
NXNL1	SP3	Q02447	696
NXNL1	BSG	P35613	667
NXNL1	ABCA4	P78363	564
NXNL1	SLC2A1	P11166	538
NXNL1	REEP6	Q96HR9	533
NXNL1	RHO	P08100	520
NXNL1	PDE6C	P51160	509
NXNL1	ARR3	P36575	474
NXNL1	CFAP418	Q96NL8	456
NXNL1	PDE6H	Q13956	453

IntAct

5 interactions, top by confidence:

A	B	Type	Score
NXNL1	TERF1	psi-mi:“MI:0915”(physical association)	0.370
NXNL1	TERF2	psi-mi:“MI:0915”(physical association)	0.370
NXNL1	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
NXNL1	POT1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (4): NXNL1 (Two-hybrid), NXNL1 (Two-hybrid), NXNL1 (Two-hybrid), NXNL1 (Two-hybrid)

ESM2 similar proteins: A0JM23, A5PMF7, B8JKF4, F4JZJ2, O23052, O60502, O77560, P0CF65, P0CI65, P19632, P20941, P20942, P41686, Q008S8, Q0P564, Q13371, Q2HJA9, Q2TBM9, Q3U213, Q568B8, Q58CZ2, Q5FVM7, Q5R7K4, Q5RCM7, Q5SNQ7, Q5ZKZ4, Q63737, Q68EV9, Q692V3, Q6AZT7, Q6P3V7, Q6P5D8, Q75BD8, Q80TN4, Q8BHD8, Q8S8L9, Q8VC33, Q8VIJ5, Q8VZQ0, Q94HV8

Diamond homologs: A5PMF7, Q5VZ03, Q68EV9, Q8VC33, Q96CM4, Q9D531, A0RBT0, A6QLU8, O77404, O80763, P80579, P97346, Q0JIL1, Q42403, Q503L9, Q63DQ8, Q6DKJ4, Q6GM16, Q6HL81, Q73B22, Q75GM1, Q7XPE8, Q7Y0E8, Q7Y0F2, Q81FU5, Q81SZ9, Q8CXF3, Q8VZQ0, Q93VQ9, Q9KCJ4, Q6NQN8, P43221

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

56 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	13
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

351 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17460538:CCTCA:C	donor_loss	1.0000
19:17460539:CTCA:C	donor_loss	1.0000
19:17460539:CTCAC:C	donor_loss	1.0000
19:17460540:TCA:T	donor_loss	1.0000
19:17460541:CACCT:C	donor_loss	1.0000
19:17460542:ACCT:A	donor_gain	1.0000
19:17460543:CCTC:C	donor_gain	1.0000
19:17460545:T:TA	donor_gain	1.0000
19:17460556:T:TA	donor_gain	1.0000
19:17460592:T:TA	donor_gain	1.0000
19:17455704:G:A	donor_gain	0.9900
19:17455714:G:GA	donor_gain	0.9900
19:17455718:TTTCC:T	donor_gain	0.9900
19:17455730:A:AC	donor_gain	0.9900
19:17455731:C:CC	donor_gain	0.9900
19:17455955:GGTCC:G	acceptor_gain	0.9900
19:17455957:TCC:T	acceptor_gain	0.9900
19:17455958:CC:C	acceptor_gain	0.9900
19:17455958:CCC:C	acceptor_gain	0.9900
19:17455958:CCCTG:C	acceptor_loss	0.9900
19:17455959:CC:C	acceptor_gain	0.9900
19:17455960:C:A	acceptor_loss	0.9900
19:17455960:C:CC	acceptor_gain	0.9900
19:17460543:CCT:C	donor_gain	0.9900
19:17455956:GTCC:G	acceptor_gain	0.9800
19:17460542:A:AC	donor_gain	0.9800
19:17460543:C:CC	donor_gain	0.9800
19:17457740:CTAGT:C	donor_gain	0.9700
19:17460542:ACCTC:A	donor_gain	0.9700
19:17460543:CCTCC:C	donor_gain	0.9700

AlphaMissense

1375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17455830:C:A	W152C	0.992
19:17455830:C:G	W152C	0.992
19:17455832:A:G	W152R	0.986
19:17455832:A:T	W152R	0.986
19:17460578:A:G	W98R	0.985
19:17460578:A:T	W98R	0.985
19:17455864:A:G	I141T	0.983
19:17460753:A:C	F39L	0.979
19:17460753:A:T	F39L	0.979
19:17460755:A:G	F39L	0.979
19:17455831:C:G	W152S	0.978
19:17455918:A:T	V123D	0.976
19:17455842:G:C	C148W	0.974
19:17460675:G:C	F65L	0.972
19:17460675:G:T	F65L	0.972
19:17460677:A:G	F65L	0.972
19:17455864:A:C	I141S	0.970
19:17455941:G:C	F115L	0.969
19:17455941:G:T	F115L	0.969
19:17455943:A:G	F115L	0.969
19:17460629:C:G	D81H	0.969
19:17460699:G:C	F57L	0.969
19:17460699:G:T	F57L	0.969
19:17460701:A:G	F57L	0.969
19:17455843:C:T	C148Y	0.968
19:17455839:G:C	F149L	0.963
19:17455839:G:T	F149L	0.963
19:17455841:A:G	F149L	0.963
19:17460634:G:A	S79F	0.963
19:17455912:A:T	V125E	0.962

dbSNP variants (sampled 300 via entrez): RS1000323488 (19:17460024 T>A), RS1000934826 (19:17462757 C>T), RS1001023981 (19:17460238 C>A,T), RS1001092077 (19:17457106 A>C), RS1001564523 (19:17457331 A>C), RS1002224830 (19:17457840 C>A,T), RS1002765924 (19:17457681 C>A), RS1002841185 (19:17459637 C>A,T), RS1003111836 (19:17454976 G>A), RS1003391511 (19:17460277 C>G,T), RS1003634839 (19:17459036 C>T), RS1003832595 (19:17456938 A>G), RS1003843935 (19:17457217 A>G), RS1004268403 (19:17457867 G>A), RS1004593461 (19:17456822 A>C)

Disease associations

OMIM: gene MIM:608791 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber congenital amaurosis	Limited	Unknown

Mondo (1): Leber congenital amaurosis (MONDO:0018998)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

22 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT03913143	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT00749957	PHASE1/PHASE2	COMPLETED	Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis
NCT01208389	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2
NCT01496040	PHASE1/PHASE2	COMPLETED	Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65
NCT02781480	PHASE1/PHASE2	COMPLETED	Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA)
NCT03913130	PHASE1/PHASE2	TERMINATED	Extension Study to Study PQ-110-001 (NCT03140969)
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT05203939	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis
NCT05906953	PHASE1/PHASE2	RECRUITING	Safety and Efficacy Trial of HG004 for Leber Congenital Amaurosis Related to Rpe65 Gene Mutations (STAR)
NCT06088992	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Leber Congenital Amaurosis Inherited Blindness of Gene Therapy Trial(LIGHT)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02575430	Not specified	COMPLETED	Natural History Study in Inherited Retinal Disease Subjects Caused by Mutations in RPE65 or LRAT
NCT02714816	Not specified	COMPLETED	Natural History Study of Patients With Leber Congenital Amaurosis Associated With Mutations in RPE65
NCT02946879	Not specified	COMPLETED	Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65)
NCT02970266	Not specified	COMPLETED	Genetic Decryption of Leber Congenital Amaurosis (LCA) in a Large Cohort of Independent Families.
NCT07026565	Not specified	NOT_YET_RECRUITING	Psychotherapy Group for Parents of Children With LCA