NHLRC2

Summary

NHLRC2 (NHL repeat containing 2, HGNC:24731) is a protein-coding gene on chromosome 10q25.3, encoding NHL repeat-containing protein 2 (Q8NBF2). Required for normal embryonic development. It is a selective cancer dependency (DepMap: 68.5% of cell lines).

Located in cytosol.

Source: NCBI Gene 374354 — RefSeq curated summary.

At a glance

• Gene–disease (curated): fibrosis, neurodegeneration, and cerebral angiomatosis (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 117 total — 5 pathogenic, 2 likely-pathogenic
• Cancer dependency (DepMap): dependent in 68.5% of screened cell lines
• MANE Select transcript: NM_198514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24731
Approved symbol	NHLRC2
Name	NHL repeat containing 2
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25621, FLJ20147, FLJ33312, MGC45492, DKFZp779F115
Ensembl gene	ENSG00000196865
Ensembl biotype	protein_coding
OMIM	618277
Entrez	374354

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000369301, ENST00000468890, ENST00000866165, ENST00000866166, ENST00000918088

RefSeq mRNA: 1 — MANE Select: NM_198514 NM_198514

CCDS: CCDS7585

Canonical transcript exons

ENST00000369301 — 11 exons

Exon	Start	End
ENSE00001000237	113901666	113901897
ENSE00001000238	113904817	113905036
ENSE00001000239	113903527	113903736
ENSE00001169513	113902471	113902593
ENSE00001169528	113898110	113898209
ENSE00001169534	113884251	113884380
ENSE00001169543	113879574	113879695
ENSE00001169553	113876521	113876976
ENSE00001169558	113858528	113858680
ENSE00001449446	113854661	113855050
ENSE00001513885	113908280	113917194

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 90.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8180 / max 157.8898, expressed in 1753 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107141	9.1096	1746
107144	0.5583	290
107142	0.0804	27
107143	0.0697	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	90.56	gold quality
choroid plexus epithelium	UBERON:0003911	90.32	gold quality
parietal pleura	UBERON:0002400	89.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.63	silver quality
pleura	UBERON:0000977	89.40	gold quality
seminal vesicle	UBERON:0000998	88.99	gold quality
mammary duct	UBERON:0001765	88.11	gold quality
epithelium of mammary gland	UBERON:0003244	87.32	gold quality
tibia	UBERON:0000979	87.03	gold quality
germinal epithelium of ovary	UBERON:0001304	86.68	gold quality
skin of hip	UBERON:0001554	86.17	gold quality
caput epididymis	UBERON:0004358	85.84	gold quality
lower lobe of lung	UBERON:0008949	85.71	gold quality
cauda epididymis	UBERON:0004360	85.62	gold quality
epithelium of nasopharynx	UBERON:0001951	85.31	gold quality
urethra	UBERON:0000057	85.24	gold quality
jejunum	UBERON:0002115	85.11	gold quality
corpus epididymis	UBERON:0004359	85.02	gold quality
cardiac ventricle	UBERON:0002082	84.91	gold quality
heart left ventricle	UBERON:0002084	84.89	gold quality
blood vessel layer	UBERON:0004797	84.81	gold quality
thoracic mammary gland	UBERON:0005200	84.35	gold quality
mammary gland	UBERON:0001911	84.32	gold quality
pigmented layer of retina	UBERON:0001782	84.31	gold quality
cardia of stomach	UBERON:0001162	84.11	gold quality
adrenal tissue	UBERON:0018303	84.06	gold quality
calcaneal tendon	UBERON:0003701	83.96	gold quality
heart	UBERON:0000948	83.93	gold quality
jejunal mucosa	UBERON:0000399	83.91	gold quality
endothelial cell	CL:0000115	83.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.00
E-CURD-10	no	307.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

211 targeting NHLRC2, 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-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 68.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• Reactive oxygen species-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cells. (PMID:29242562)
• Study identified a novel cerebropulmonary and multi-organ disease characterised by a unique combination of tissue fibrosis, neurodegeneration and cerebral angiomatosis, and identified identical compound heterozygous NHLRC2 variants in three affected children from two unrelated families. Also created a KO mouse model and zebrafish morphants to investigate the consequences of absent or decreased Nhlrc2 expression. (PMID:29423877)
• Bioinformatics analysis discovers homologs across a range of eukaryotic and prokaryotic species and conserved residues map mostly to the adjacent surfaces of the Trx-like and beta-propeller domains that form the cleft, suggesting both that this forms the potential functional site of NHLRC2 and that the function is conserved across species. (PMID:30138417)
• We conclude that compound heterozygous p.Asp148Tyr and p.Arg201GlyfsTer6 mutations in NHLRC2 lead to severe tissue fibrosis in humans by enhancing the differentiation of fibroblasts to myofibroblasts. (PMID:30239752)
• Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome. (PMID:32435055)
• NHLRC2 expression is increased in idiopathic pulmonary fibrosis. (PMID:35964085)
• Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals. (PMID:37188825)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhlrc2	ENSDARG00000089581
mus_musculus	Nhlrc2	ENSMUSG00000025078
rattus_norvegicus	Nhlrc2	ENSRNOG00000016948
drosophila_melanogaster	CG12547	FBGN0250830

Protein

Protein identifiers

NHL repeat-containing protein 2 — Q8NBF2 (reviewed: Q8NBF2)

All UniProt accessions (1): Q8NBF2

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal embryonic development.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous. Detected in heart, kidney, muscle, brain, lung, liver and in skin fibroblasts (at protein level).

Disease relevance. Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) [MIM:618278] An autosomal recessive, early-onset and fatal disorder clinically characterized by progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia and transient liver dysfunction. Death occurs in the first years of life due to respiratory failure. Post-mortem neuropathological examination reveals increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are observed in the lungs. Hepatomegaly, steatosis and collagen accumulation are detected in the liver. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NBF2-1	1	yes
Q8NBF2-2	2

RefSeq proteins (1): NP_940916* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001258	NHL_repeat	Repeat
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR012336	Thioredoxin-like_fold	Domain
IPR013766	Thioredoxin_domain	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR045302	NHL2_NHL_rpt_dom	Domain

Pfam: PF01436, PF13905

UniProt features (76 total): strand 35, helix 19, turn 10, repeat 6, sequence variant 2, chain 1, domain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6G7W	X-RAY DIFFRACTION	1.75
6GC1	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBF2-F1	92.96	0.83

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation

MSigDB gene sets: 256 (showing top): E2F_Q4_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, AML_Q6, WTGAAAT_UNKNOWN, GARY_CD5_TARGETS_DN, DOUGLAS_BMI1_TARGETS_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, AML1_01, E2F_Q6_01

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), cytosol (GO:0005829), platelet alpha granule lumen (GO:0031093), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	1
cytoplasm	1
platelet alpha granule	1
secretory granule lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2127 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHLRC2	TM2D3	Q9BRN9	625
NHLRC2	CCDC186	Q7Z3E2	566
NHLRC2	TM2D2	Q9BX73	566
NHLRC2	TM2D1	Q9BX74	566
NHLRC2	VWA2	Q5GFL6	561
NHLRC2	DCLRE1A	Q6PJP8	503
NHLRC2	LAMTOR2	Q9Y2Q5	475
NHLRC2	PLEKHS1	Q5SXH7	475
NHLRC2	TECTB	Q96PL2	466
NHLRC2	ZDHHC6	Q9H6R6	460
NHLRC2	ADRB1	P08588	450
NHLRC2	CDADC1	Q9BWV3	442
NHLRC2	NAA30	Q147X3	428
NHLRC2	LAMTOR4	Q0VGL1	425
NHLRC2	ABLIM1	O14639	424

IntAct

25 interactions, top by confidence:

A	B	Type	Score
CEP76	NHLRC2	psi-mi:“MI:0915”(physical association)	0.670
NHLRC2	CEP76	psi-mi:“MI:0915”(physical association)	0.670
NHLRC2	CEP76	psi-mi:“MI:0914”(association)	0.670
ISX	MOCS3	psi-mi:“MI:0914”(association)	0.530
MSL2	NHLRC2	psi-mi:“MI:0915”(physical association)	0.400
NHLRC2	iglC2	psi-mi:“MI:0915”(physical association)	0.370
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
TAFA3	FUOM	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
ZBTB3	VWA8	psi-mi:“MI:0914”(association)	0.350
SRSF2	PARN	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
KANSL3	GSPT1	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
ORF24	MVK	psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
HRAS	IGHV1-45	psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (399): NHLRC2 (Two-hybrid), NHLRC2 (Co-fractionation), NHLRC2 (Affinity Capture-MS), NHLRC2 (Two-hybrid), NHLRC2 (Affinity Capture-MS), ERC1 (Affinity Capture-MS), NHLRC2 (Affinity Capture-MS), NHLRC2 (Affinity Capture-MS), NHLRC2 (Proximity Label-MS), NHLRC2 (Positive Genetic), NHLRC2 (Affinity Capture-RNA), AHCY (Affinity Capture-MS), ALDH9A1 (Affinity Capture-MS), ALK (Affinity Capture-MS), ANXA4 (Affinity Capture-MS)

ESM2 similar proteins: A0JMU5, A0JPF9, A1A4L5, A4IF69, G3GXG9, O43933, O70362, P19686, P57075, P80108, P80109, Q02108, Q0V9N0, Q14703, Q28CZ7, Q2TBM9, Q3B7N1, Q3U213, Q3U3W5, Q3UY23, Q4ZHS0, Q5BL07, Q5XFW6, Q5ZI67, Q5ZKL5, Q6NRS1, Q6P2P2, Q6ZPR6, Q80Y20, Q86WJ1, Q8BGG7, Q8BWR4, Q8BZW8, Q8C042, Q8L735, Q8LEV3, Q8NBF2, Q8R2H5, Q8TF42, Q8VZ10

Diamond homologs: A4IF69, Q5ZI67, Q8BZW8, Q8NBF2, Q8VZ10, O31430, O31699, P59960, P9WG62, P9WG63, O33513, P35160, P40119, P54607, P65070, P71447, P77247, P95649, P9WKZ6, P9WKZ7, Q04541, Q15JF8, Q49741, Q6HL81, Q73B22, Q7ADF8, Q81FU5, Q94529, Q94K71, Q9X0Y1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	76
Likely benign	15
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1279930	NM_198514.4(NHLRC2):c.224A>T (p.Asp75Val)	Pathogenic
1279931	NM_198514.4(NHLRC2):c.1013C>T (p.Pro338Leu)	Pathogenic
1279932	NM_198514.4(NHLRC2):c.428A>C (p.His143Pro)	Pathogenic
599377	NM_198514.4(NHLRC2):c.442G>T (p.Asp148Tyr)	Pathogenic
599378	NM_198514.4(NHLRC2):c.601_602del (p.Arg201fs)	Pathogenic
1690893	NM_198514.4(NHLRC2):c.278_279del (p.Cys93fs)	Likely pathogenic
1727060	NM_198514.4(NHLRC2):c.1750del (p.Phe583_Leu584insTer)	Likely pathogenic

SpliceAI

2276 predictions. Top by Δscore:

Variant	Effect	Δscore
10:113855023:G:GT	donor_gain	1.0000
10:113855034:ACCCG:A	donor_gain	1.0000
10:113855047:G:GT	donor_gain	1.0000
10:113855048:A:T	donor_gain	1.0000
10:113855048:AAGGT:A	donor_loss	1.0000
10:113855049:AGG:A	donor_loss	1.0000
10:113855051:G:GA	donor_loss	1.0000
10:113865543:A:G	donor_gain	1.0000
10:113876515:TTTCA:T	acceptor_loss	1.0000
10:113876517:TCA:T	acceptor_loss	1.0000
10:113876518:CAG:C	acceptor_loss	1.0000
10:113876519:AG:A	acceptor_loss	1.0000
10:113876519:AGAT:A	acceptor_gain	1.0000
10:113876520:G:A	acceptor_loss	1.0000
10:113876520:G:GA	acceptor_gain	1.0000
10:113876520:GAT:G	acceptor_gain	1.0000
10:113876520:GATG:G	acceptor_gain	1.0000
10:113876652:C:T	donor_gain	1.0000
10:113876661:G:GT	donor_gain	1.0000
10:113879570:TTAGG:T	acceptor_loss	1.0000
10:113879572:A:AC	acceptor_loss	1.0000
10:113879572:A:AG	acceptor_gain	1.0000
10:113879573:G:GA	acceptor_loss	1.0000
10:113879573:G:GG	acceptor_gain	1.0000
10:113879691:GAAAG:G	donor_gain	1.0000
10:113879695:GGTAA:G	donor_loss	1.0000
10:113879696:G:C	donor_loss	1.0000
10:113879697:T:A	donor_loss	1.0000
10:113902457:A:AG	acceptor_gain	1.0000
10:113902458:A:AG	acceptor_gain	1.0000

AlphaMissense

4736 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:113901722:G:C	R399P	0.999
10:113901701:G:A	G392E	0.998
10:113901814:G:C	D430H	0.998
10:113901836:G:C	R437T	0.998
10:113901837:A:C	R437S	0.998
10:113901837:A:T	R437S	0.998
10:113876556:T:C	F123L	0.997
10:113876558:T:A	F123L	0.997
10:113876558:T:G	F123L	0.997
10:113901826:A:C	S434R	0.997
10:113901828:T:A	S434R	0.997
10:113901828:T:G	S434R	0.997
10:113898167:T:A	I366K	0.996
10:113901823:A:C	S433R	0.996
10:113901825:C:A	S433R	0.996
10:113901825:C:G	S433R	0.996
10:113876913:G:C	D242H	0.995
10:113879669:G:C	D295H	0.995
10:113879688:T:A	I301K	0.995
10:113898164:A:C	Q365P	0.995
10:113898169:T:A	W367R	0.995
10:113898169:T:C	W367R	0.995
10:113901698:C:A	A391D	0.995
10:113901726:C:A	N400K	0.995
10:113901726:C:G	N400K	0.995
10:113901836:G:T	R437I	0.995
10:113902483:T:C	F462L	0.995
10:113902485:T:A	F462L	0.995
10:113902485:T:G	F462L	0.995
10:113898167:T:G	I366R	0.994

dbSNP variants (sampled 300 via entrez): RS1000000174 (10:113867079 A>C), RS1000092831 (10:113906681 T>C), RS1000154313 (10:113885777 C>T), RS1000231011 (10:113911674 G>A,C), RS1000276103 (10:113855076 G>A,T), RS1000325648 (10:113872959 A>G), RS1000380808 (10:113879352 G>A), RS1000427023 (10:113873204 G>A), RS1000430410 (10:113873114 A>G), RS1000480813 (10:113871621 C>G), RS1000484103 (10:113898033 A>C), RS1000567825 (10:113854625 G>A,C,T), RS1000595699 (10:113891081 G>T), RS1000611459 (10:113867033 T>C), RS1000616707 (10:113865316 C>T)

Disease associations

OMIM: gene MIM:618277 | disease phenotypes: MIM:618278

GenCC curated gene-disease

Disease	Classification	Inheritance
fibrosis, neurodegeneration, and cerebral angiomatosis	Definitive	Autosomal recessive

Mondo (1): fibrosis, neurodegeneration, and cerebral angiomatosis (MONDO:0032651)

Orphanet (1): Fibrosis-neurodegeneration-cerebral angiomatosis syndrome (Orphanet:621758)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90011899_51	Aspartate aminotransferase levels	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
decabromobiphenyl ether	increases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
2-butenal	decreases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
avobenzone	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Coal	decreases expression, increases abundance	1
Curcumin	decreases expression	1
Demecolcine	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, decreases expression	1
Hydrogen Peroxide	increases expression	1
Ivermectin	decreases expression	1

Clinical trials (associated diseases)

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