NUS1

Summary

NUS1 (NUS1 dehydrodolichyl diphosphate synthase subunit, HGNC:21042) is a protein-coding gene on chromosome 6q22.1, encoding Dehydrodolichyl diphosphate synthase complex subunit NUS1 (Q96E22). With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a type I single transmembrane domain receptor, which is a subunit of cis-prenyltransferase, and serves as a specific receptor for the neural and cardiovascular regulator Nogo-B. The encoded protein is essential for dolichol synthesis and protein glycosylation. This gene is highly expressed in non-small cell lung carcinomas as well as estrogen receptor-alpha positive breast cancer cells where it promotes epithelial mesenchymal transition. This gene is associated with the poor prognosis of human hepatocellular carcinoma patients. Naturally occurring mutations in this gene cause a congenital disorder of glycosylation and are associated with epilepsy. A knockout of the orthologous gene in mice causes embryonic lethality before day 6.5. Pseudogenes of this gene have been defined on chromosomes 13 and X.

Source: NCBI Gene 116150 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive myoclonus epilepsy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 505 total — 55 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 74
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_138459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21042
Approved symbol	NUS1
Name	NUS1 dehydrodolichyl diphosphate synthase subunit
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC7199, NgBR, TANGO14
Ensembl gene	ENSG00000153989
Ensembl biotype	protein_coding
OMIM	610463
Entrez	116150

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000368494, ENST00000885063, ENST00000923852

RefSeq mRNA: 1 — MANE Select: NM_138459 NM_138459

CCDS: CCDS5118

Canonical transcript exons

ENST00000368494 — 5 exons

Exon	Start	End
ENSE00001013416	117693042	117693167
ENSE00001084583	117703605	117703704
ENSE00001295943	117694031	117694180
ENSE00001447271	117706925	117710727
ENSE00001447272	117675469	117676085

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 94.96.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9676 / max 10.6730, expressed in 702 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69455	0.9676	702

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium	UBERON:0001295	94.96	gold quality
tibia	UBERON:0000979	94.06	gold quality
islet of Langerhans	UBERON:0000006	94.05	gold quality
kidney epithelium	UBERON:0004819	93.94	gold quality
upper arm skin	UBERON:0004263	93.09	gold quality
cartilage tissue	UBERON:0002418	92.79	gold quality
ileal mucosa	UBERON:0000331	92.59	gold quality
oocyte	CL:0000023	92.38	gold quality
nasal cavity mucosa	UBERON:0001826	92.36	gold quality
nasal cavity epithelium	UBERON:0005384	92.33	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.23	gold quality
palpebral conjunctiva	UBERON:0001812	91.97	gold quality
corpus epididymis	UBERON:0004359	91.47	gold quality
left ventricle myocardium	UBERON:0006566	91.43	gold quality
monocyte	CL:0000576	91.34	gold quality
leukocyte	CL:0000738	91.16	gold quality
epithelial cell of pancreas	CL:0000083	90.90	silver quality
cortical plate	UBERON:0005343	90.90	gold quality
endothelial cell	CL:0000115	90.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.49	gold quality
caput epididymis	UBERON:0004358	90.48	gold quality
upper leg skin	UBERON:0004262	90.32	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.26	gold quality
pancreas	UBERON:0001264	90.20	gold quality
parotid gland	UBERON:0001831	89.96	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.94	gold quality
secondary oocyte	CL:0000655	89.84	gold quality
parietal pleura	UBERON:0002400	89.81	gold quality
oviduct epithelium	UBERON:0004804	89.78	gold quality
stromal cell of endometrium	CL:0002255	89.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

201 targeting NUS1, 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-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 36)

• identify a previously uncharacterized Nogo-B receptor specific for the amino terminus of Nogo-B (PMID:16835300)
• In s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A beta production. However, the increase of Nogo-B seems insufficient because A beta continues to accumulate and the disease progresses. (PMID:17764014)
• The Nogo-B receptor localizes primarily to the endoplasmic reticulum and regulates the stability of nascent Niemann-Pick type C2 protein. (PMID:19723497)
• Nogo-B receptor (NgBR) is an essential component of the dolichol monophosophate (Dol-P) biosynthetic machinery. Loss of NgBR results in a robust deficit in cis-isoprenyltransferase (IPTase) activity and Dol-P production. (PMID:21572394)
• NgBR is a new molecular marker for breast cancer. (PMID:24223763)
• Nogo-B receptor mediates pulmonary endothelial cell angiogenesis response through Akt/endothelial nitric oxide synthase pathway. (PMID:24568601)
• Described is a family with a congenital disorder of glycosylation caused by a loss of function mutation in the conserved C terminus of Nogo-B receptor - R290H. (PMID:25066056)
• Significant NgBR mRNA down-regulation was associated with larger primary tumor size (p=0.039), lymph node involvement (p=0.039) and advancement stage (p=0.0054). (PMID:25075030)
• These findings provide new insights for understanding the roles of NgBR in regulating breast epithelial cell transform during the pathogenesis of breast cancer. (PMID:25173099)
• Nogo-B receptor expression correlates negatively with malignancy grade and ki-67 antigen expression in invasive ductal breast carcinoma. (PMID:25202063)
• High NgBR expression is associated with chemoresistance in hepatocellular carcinoma. (PMID:26840457)
• The data suggest that miR-26a plays a key role in VEGF-mediated angiogenesis through the modulation of eNOS activity, which is mediated by its ability to regulate NgBR expression by directly targeting the NgBR 3’-UTR. (PMID:28602162)
• findings show that eukaryotic cis-PT is composed of the NgBR and hCIT subunits. The strong conservation of the RXG motif among NgBR orthologs indicates that this subunit is critical for the synthesis of polyprenol diphosphates and cellular function. (PMID:28842490)
• Data show that Nogo-B receptor (NgBR) knockdown inhibited epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells in vitro and metastasis of NSCLC cells in vivo. (PMID:29331415)
• Small Angle X-ray Scattering (SAXS) analysis reveals the radius of gyration (Rg) of our NgBR construct to be 18.2 A with a maximum particle dimension (Dmax) of 61.0 A. Ab initio shape modeling returns a globular molecular envelope with an estimated molecular weight of 23.0 kD closely correlated with the calculated molecular weight (PMID:29346419)
• Data suggest that Nogo-B receptor (NgBR) expression is essential to promoting estrogen receptor alpha (ERalpha) positive breast cancer cell resistance to paclitaxel. (PMID:29373839)
• The Nogo-B receptor was highly expressed in human hepatocellular carcinoma (HCC) cell lines and in the tissue of patients with HCC and promoted human HCC cell growth by increasing the Akt phosphorylation in human HCC cells (PMID:29904947)
• NgBR role in cancer.NgBR is able to promote N-glycosylation to attenuate endoplasmic reticulum stress and the unfolded protein response.[review] (PMID:30106141)
• Results suggest that Nogo-B receptor (NgBR) is a potential therapeutic target for increasing the sensitivity of estrogen receptor alpha (ERalpha)-positive breast cancer to tamoxifen. (PMID:30208932)
• Coding mutations in NUS1 contribute to Parkinson’s disease. (PMID:30348779)
• NUS1 was upregulated in IUAs tissues, and the high expression level of NUS1 was positively correlated with the severity of IUAs. NUS1 promoted cell proliferation in vitro. NUS1 overexpression on cell migration and invasion promoted the EMT process in vitro and in vivo. (PMID:31154456)
• we report two unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. (PMID:31656175)
• Nogo-B fosters HCC progression by enhancing Yap/Taz-mediated tumor-associated macrophages M2 polarization. (PMID:32246992)
• NUS1 mutation in a family with epilepsy, cerebellar ataxia, and tremor. (PMID:32485575)
• Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. (PMID:32817466)
• Salivary NUS1 and RCN1 Levels as Biomarkers for Oral Squamous Cell Carcinoma Diagnosis. (PMID:32871760)
• Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex. (PMID:33077723)
• Assessment of the association between NUS1 variants and essential tremor. (PMID:33184037)
• Replication assessment of NUS1 variants in Parkinson’s disease. (PMID:33309333)
• NOGOB receptor-mediated RAS signaling pathway is a target for suppressing proliferating hemangioma. (PMID:33400686)
• Contribution of coding/non-coding variants in NUS1 to late-onset sporadic Parkinson’s disease. (PMID:33548880)
• Common Variants in NUS1 and GP2 Genes Contributed to the Risk of Gestational Diabetes Mellitus. (PMID:34326813)
• Low-frequency and rare coding variants of NUS1 contribute to susceptibility and phenotype of Parkinson’s disease. (PMID:34635350)
• Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1alpha-dependent pathway. (PMID:36241702)
• Novel NUS1 variant in a Chinese patient with progressive myoclonus epilepsy: a case report and systematic review. (PMID:37249665)
• NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation. (PMID:38520610)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nus1	ENSDARG00000027813
mus_musculus	Nus1	ENSMUSG00000023068
rattus_norvegicus	Nus1	ENSRNOG00000000411
drosophila_melanogaster	Tango14	FBGN0031312
caenorhabditis_elegans		WBGENE00009505

Protein

Protein identifiers

Dehydrodolichyl diphosphate synthase complex subunit NUS1 — Q96E22 (reviewed: Q96E22)

Alternative names: Cis-prenyltransferase subunit NgBR, Nogo-B receptor, Nuclear undecaprenyl pyrophosphate synthase 1 homolog

All UniProt accessions (1): Q96E22

UniProt curated annotations — full annotation on UniProt →

Function. With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length. Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol. Acts as a specific receptor for the N-terminus of Nogo-B, a neural and cardiovascular regulator.

Subunit / interactions. The active dehydrodolichyl diphosphate synthase complex is a heterotetramer composed of a dimer of heterodimer of DHDDS and NUS1. Interacts with NPC2.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1AA (CDG1AA) [MIM:617082] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG1AA inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, autosomal dominant 55, with seizures (MRD55) [MIM:617831] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD55 patients suffer from seizures appearing during the first years of life. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phospholipids including cardiolipin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine.

Domain organisation. Contains the RXG motif, which is important for substrate binding and prenyltransferase activity. The catalytic site at NUS1-DHDDS interface accomodates both the allylic and the homoallylic IPP substrates to the S1 and S2 pockets respectively. The beta-phosphate groups of IPP substrates form hydrogen bonds with the RXG motif of NUS1 and four conserved residues of DHDDS (‘Arg-85’, ‘Arg-205’, ‘Arg-211’ and ‘Ser-213’), while the allylic isopentenyl group is pointed toward the hydrophobic tunnel of the S1 pocket where the product elongation occurs.

Pathway. Protein modification; protein glycosylation. Lipid metabolism.

Miscellaneous. NUS1 seems to exist in two topological orientations, a minor glycosylated species with its C-terminus oriented towards the lumen regulating NPC2 stability, and a major fraction oriented with its C-terminus directed towards the cytosol where it regulates cis-IPTase activity.

Similarity. Belongs to the UPP synthase family.

RefSeq proteins (1): NP_612468* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001441	UPP_synth-like	Family
IPR036424	UPP_synth-like_sf	Homologous_superfamily
IPR038887	Nus1/NgBR	Family

Pfam: PF01255

Enzyme classification (BRENDA):

• EC 2.5.1.87 — ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] (BRENDA: 12 organisms, 23 substrates, 2 inhibitors, 13 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ISOPENTENYL DIPHOSPHATE	0.0005–0.111	6
(2E,6E)-FARNESYL DIPHOSPHATE	0.0001–0.0149	3
DIMETHYLALLYL DIPHOSPHATE	0.0094	1
FARNESYL DIPHOSPHATE	0.001	1
GERANYL DIPHOSPHATE	0.0018	1
GERANYLGERANYL DIPHOSPHATE	0.0036	1

Catalyzed reactions (Rhea), 1 shown:

• n isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = a di-trans,poly-cis-polyprenyl diphosphate + n diphosphate (RHEA:53008)

UniProt features (46 total): mutagenesis site 12, helix 11, sequence variant 8, strand 5, transmembrane region 3, binding site 2, glycosylation site 2, chain 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7PAX	X-RAY DIFFRACTION	2
6Z1N	X-RAY DIFFRACTION	2.3
7PB0	X-RAY DIFFRACTION	2.3
6W2L	X-RAY DIFFRACTION	2.31
7PAY	X-RAY DIFFRACTION	2.4
9R08	X-RAY DIFFRACTION	2.4
7PB1	X-RAY DIFFRACTION	2.59
9R0E	X-RAY DIFFRACTION	2.82
9R0K	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96E22-F1	82.01	0.59

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 291; 292

Glycosylation sites (2): 144, 271

Mutagenesis-validated functional residues (12):

Position	Phenotype
100	3.5-fold reduction in catalytic activity and no marked change in affinity for fpp and ipp.
196	decreases binding to dhdds.
197	decreases binding to dhdds.
200	disrupts nus1-dhdds heterodimerization.
226	disrupts nus1-dhdds heterodimerization.
230	disrupts nus1-dhdds heterodimerization.
252	disrupts nus1-dhdds heterodimerization.
253	disrupts nus1-dhdds heterodimerization.
255	disrupts nus1-dhdds heterodimerization.
292	almost complete loss of catalytic activity.
293	almost complete loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-446199	Synthesis of dolichyl-phosphate
R-HSA-4755609	Defective DHDDS causes RP59

MSigDB gene sets: 342 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_STEROL_HOMEOSTASIS, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION, GOBP_LIPID_HOMEOSTASIS, GOBP_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GERY_CEBP_TARGETS, GOBP_SPROUTING_ANGIOGENESIS

GO Biological Process (14): angiogenesis (GO:0001525), dolichyl diphosphate biosynthetic process (GO:0006489), cell differentiation (GO:0030154), regulation of intracellular cholesterol transport (GO:0032383), vascular endothelial growth factor signaling pathway (GO:0038084), cholesterol homeostasis (GO:0042632), dolichyl monophosphate biosynthetic process (GO:0043048), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903589), obsolete protein glycosylation (GO:0006486), lipid metabolic process (GO:0006629), obsolete dolichol biosynthetic process (GO:0019408), obsolete protein mannosylation (GO:0035268), sterol homeostasis (GO:0055092)

GO Molecular Function (6): ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity (GO:0045547), metal ion binding (GO:0046872), prenyltransferase activity (GO:0004659), protein binding (GO:0005515), transferase activity (GO:0016740), transferase activity, transferring alkyl or aryl (other than methyl) groups (GO:0016765)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), dehydrodolichyl diphosphate synthase complex (GO:1904423), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1
Diseases associated with glycosylation precursor biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phospholipid biosynthetic process	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
dolichol-linked oligosaccharide biosynthetic process	1
cellular developmental process	1
intracellular cholesterol transport	1
regulation of cholesterol transport	1
regulation of intracellular sterol transport	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to vascular endothelial growth factor stimulus	1
sterol homeostasis	1
cell migration involved in sprouting angiogenesis	1
positive regulation of blood vessel endothelial cell migration	1
regulation of cell migration involved in sprouting angiogenesis	1
positive regulation of endothelial cell proliferation	1
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1
regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1
primary metabolic process	1
lipid homeostasis	1
prenyl diphosphate synthase activity	1
cation binding	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
binding	1
catalytic activity	1
transferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
polyprenyl diphosphate synthase complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1904 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUS1	RTN4	Q9NQC3	920
NUS1	DHDDS	Q86SQ9	905
NUS1	RTN3	O95197	678
NUS1	RTN2	O75298	676
NUS1	RTN4R	Q9BZR6	669
NUS1	REEP5	Q00765	669
NUS1	RTN1	Q16799	651
NUS1	SRD5A3	Q9H8P0	646
NUS1	DOLK	Q9UPQ8	638
NUS1	MAG	P20916	594
NUS1	MPDU1	O75352	592
NUS1	DOLPP1	Q86YN1	592
NUS1	OMG	P23515	569
NUS1	CAV1	Q03135	553
NUS1	ZNF770	Q6IQ21	507

IntAct

64 interactions, top by confidence:

A	B	Type	Score
DHDDS	NUS1	psi-mi:“MI:0407”(direct interaction)	0.730
DHDDS	NUS1	psi-mi:“MI:0915”(physical association)	0.730
HLA-C	HLA-A	psi-mi:“MI:0914”(association)	0.670
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
NUS1	POTEI	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
NUS1	HSPA8	psi-mi:“MI:0914”(association)	0.530
RTN4	NUS1	psi-mi:“MI:0915”(physical association)	0.400
C10orf95	NUS1	psi-mi:“MI:0915”(physical association)	0.400
NUS1	C10orf95	psi-mi:“MI:0915”(physical association)	0.400
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
LRRTM1	TMEM223	psi-mi:“MI:0914”(association)	0.350
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DPA1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
KCNC4	GXYLT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (90): NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Proximity Label-MS), NUS1 (Proximity Label-MS), NUS1 (Affinity Capture-MS), POTEI (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), NUS1 (Affinity Capture-MS), ACTB (Affinity Capture-MS)

ESM2 similar proteins: A2XK30, A2YA15, A3BLS0, A4IFB4, D3YY23, O09017, O88444, P0C0M2, P10588, P19754, P43136, Q08828, Q0D4Z6, Q0DWC7, Q10KF5, Q10PI9, Q17RB8, Q2R3B4, Q53JI9, Q53P49, Q5GA22, Q5NAZ7, Q5SML4, Q60EJ6, Q60EY1, Q654M1, Q69XK5, Q6AST1, Q6ATB2, Q6T5K2, Q6T5K3, Q6YYZ1, Q6Z690, Q6ZLA3, Q6ZLA7, Q75IS2, Q7F239, Q7PC71, Q7XUT9, Q7XUU0

Diamond homologs: Q6DHR8, Q89KP7, Q96E22, Q99LJ8, O84456, Q5V1I1, Q7U7P7, Q98MB9, Q9Y7K8, Q57CY1, Q7MXJ4, Q82IC1, Q87EH7, Q8FQR4, Q8G0D9, Q8YHH3, Q9PEH8, Q9Z7Y7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	26
Uncertain significance	234
Likely benign	153
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1011945	NC_000006.11:g.(?118028088)(118028178_?)del	Pathogenic
1351781	NM_138459.5(NUS1):c.765_769dup (p.His257fs)	Pathogenic
1386407	NM_138459.5(NUS1):c.15C>A (p.Tyr5Ter)	Pathogenic
1453662	NM_138459.5(NUS1):c.74_75delinsAA (p.Trp25Ter)	Pathogenic
1460025	NC_000006.11:g.(?118014185)(118014350_?)del	Pathogenic
1690323	NM_138459.5(NUS1):c.25_26del (p.Trp9fs)	Pathogenic
1699400	NM_138459.5(NUS1):c.99G>A (p.Trp33Ter)	Pathogenic
1878519	NM_138459.5(NUS1):c.405C>G (p.Tyr135Ter)	Pathogenic
2002848	NM_138459.5(NUS1):c.250dup (p.Arg84fs)	Pathogenic
2101645	NM_138459.5(NUS1):c.695C>G (p.Ser232Ter)	Pathogenic
2112620	NM_138459.5(NUS1):c.482del (p.Gly161fs)	Pathogenic
2427241	NC_000006.11:g.(?117996834)(117997268_?)del	Pathogenic
2505167	NM_138459.5(NUS1):c.791+6T>G	Pathogenic
2506517	NM_138459.5(NUS1):c.48_49del (p.Cys17fs)	Pathogenic
2577019	NM_138459.5(NUS1):c.128_141del (p.Ala43fs)	Pathogenic
2583160	NM_138459.5(NUS1):c.472G>T (p.Glu158Ter)	Pathogenic
2747349	NM_138459.5(NUS1):c.234_280dup (p.Leu94fs)	Pathogenic
2758134	NM_138459.5(NUS1):c.378del (p.Val127fs)	Pathogenic
2769035	NM_138459.5(NUS1):c.836_837dup (p.Ala280fs)	Pathogenic
2822088	NM_138459.5(NUS1):c.565A>T (p.Lys189Ter)	Pathogenic
2838328	NM_138459.5(NUS1):c.368_372del (p.Trp123fs)	Pathogenic
2851443	NM_138459.5(NUS1):c.415+2T>G	Pathogenic
2851556	NM_138459.5(NUS1):c.110G>A (p.Trp37Ter)	Pathogenic
2852858	NM_138459.5(NUS1):c.225del (p.Ser76fs)	Pathogenic
2860526	NM_138459.5(NUS1):c.94_101del (p.Thr32fs)	Pathogenic
2866116	NM_138459.5(NUS1):c.119_132dup (p.Ser45fs)	Pathogenic
3246047	NC_000006.11:g.(?117996834)(118028178_?)del	Pathogenic
3254587	NM_138459.5(NUS1):c.647dup (p.Arg217fs)	Pathogenic
3337414	NM_138459.5(NUS1):c.5del (p.Thr2fs)	Pathogenic
3377426	NM_138459.5(NUS1):c.51T>A (p.Cys17Ter)	Pathogenic

SpliceAI

923 predictions. Top by Δscore:

Variant	Effect	Δscore
6:117676084:AGGTG:A	donor_loss	1.0000
6:117676085:GGTGA:G	donor_loss	1.0000
6:117676086:G:T	donor_loss	1.0000
6:117676087:T:G	donor_loss	1.0000
6:117693037:TAAA:T	acceptor_loss	1.0000
6:117693037:TAAAG:T	acceptor_gain	1.0000
6:117693038:A:AG	acceptor_gain	1.0000
6:117693038:AAAG:A	acceptor_gain	1.0000
6:117693038:AAAGG:A	acceptor_gain	1.0000
6:117693039:A:G	acceptor_gain	1.0000
6:117693040:A:AC	acceptor_loss	1.0000
6:117693040:A:G	acceptor_gain	1.0000
6:117693041:G:GT	acceptor_gain	1.0000
6:117693041:GGT:G	acceptor_gain	1.0000
6:117693041:GGTA:G	acceptor_gain	1.0000
6:117693041:GGTAT:G	acceptor_gain	1.0000
6:117693165:AAGGT:A	donor_loss	1.0000
6:117693166:AG:A	donor_gain	1.0000
6:117693167:GG:G	donor_gain	1.0000
6:117693168:G:GA	donor_loss	1.0000
6:117693168:G:GG	donor_gain	1.0000
6:117693169:T:G	donor_loss	1.0000
6:117694029:A:AG	acceptor_gain	1.0000
6:117694030:G:GA	acceptor_gain	1.0000
6:117694030:GT:G	acceptor_gain	1.0000
6:117694030:GTT:G	acceptor_gain	1.0000
6:117694030:GTTT:G	acceptor_gain	1.0000
6:117694030:GTTTT:G	acceptor_gain	1.0000
6:117694116:G:GG	donor_gain	1.0000
6:117694153:G:GT	donor_gain	1.0000

AlphaMissense

1908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:117703679:T:A	W256R	0.997
6:117703679:T:C	W256R	0.997
6:117676067:A:C	S133R	0.996
6:117676069:C:A	S133R	0.996
6:117676069:C:G	S133R	0.996
6:117703695:C:T	T261I	0.996
6:117675963:C:A	P98H	0.993
6:117676037:T:A	W123R	0.993
6:117676037:T:C	W123R	0.993
6:117693069:T:C	L148S	0.993
6:117676071:T:A	V134D	0.991
6:117703638:T:C	L242S	0.990
6:117703670:T:C	F253L	0.990
6:117703671:T:C	F253S	0.990
6:117703672:T:A	F253L	0.990
6:117703672:T:G	F253L	0.990
6:117676023:C:A	A118E	0.988
6:117703632:T:C	L240S	0.988
6:117675974:G:C	G102R	0.987
6:117676040:T:C	C124R	0.987
6:117694100:C:A	A204D	0.987
6:117703658:A:C	S249R	0.987
6:117703660:C:A	S249R	0.987
6:117703660:C:G	S249R	0.987
6:117676077:A:T	D136V	0.986
6:117703681:G:C	W256C	0.986
6:117703681:G:T	W256C	0.986
6:117707001:C:A	R290S	0.986
6:117675962:C:T	P98S	0.985
6:117676042:T:G	C124W	0.985

dbSNP variants (sampled 300 via entrez): RS1000205837 (6:117691883 C>G,T), RS1000244285 (6:117697046 T>C), RS1000244665 (6:117682786 A>G), RS1000246708 (6:117677531 C>T), RS1000415046 (6:117702322 G>A), RS1000505759 (6:117690310 C>T), RS1000585047 (6:117695675 G>C), RS1000663107 (6:117700742 G>A), RS1000766030 (6:117702658 T>C), RS1000895285 (6:117711081 G>A), RS1001048181 (6:117694723 C>T), RS1001259886 (6:117707358 G>A), RS1001334417 (6:117697968 C>G), RS1001337644 (6:117689590 T>C), RS1001437692 (6:117696279 C>G)

Disease associations

OMIM: gene MIM:610463 | disease phenotypes: MIM:617082, MIM:617831

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 55, with seizures	Definitive	Autosomal dominant
congenital disorder of glycosylation, type IAA	Strong	Autosomal recessive
progressive myoclonus epilepsy	Strong	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
progressive myoclonus epilepsy	Definitive	AD

Mondo (7): congenital disorder of glycosylation, type IAA (MONDO:0014904), intellectual disability, autosomal dominant 55, with seizures (MONDO:0030921), congenital disorder of glycosylation (MONDO:0015286), bilateral perisylvian polymicrogyria (MONDO:0020340), microcephaly (MONDO:0001149), undetermined early-onset epileptic encephalopathy (MONDO:0018614), progressive myoclonus epilepsy (MONDO:0020074)

Orphanet (2): Congenital disorder of glycosylation (Orphanet:137), Bilateral perisylvian polymicrogyria (Orphanet:98889)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000998	Hypertrichosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007267_220	Systolic blood pressure	9.000000e-09
GCST007847_76	Type 2 diabetes	8.000000e-12
GCST010118_138	Type 2 diabetes	8.000000e-13
GCST90000582_15	Spontaneous coronary artery dissection	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	increases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
afimoxifene	decreases expression	1
cobaltous chloride	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	decreases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	affects expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Glucosamine	increases phosphorylation, increases expression, increases splicing, increases reaction, decreases reaction	1
Methyl Methanesulfonate	decreases expression	1
Plant Oils	increases expression	1
Thiram	increases expression	1
Cadmium Chloride	increases expression, increases abundance	1
Lactic Acid	increases expression	1
Raloxifene Hydrochloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT06593951	Not specified	RECRUITING	Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)
NCT06923241	Not specified	COMPLETED	Nutri-score Labelling in a UK Restaurant Setting: a Randomised Control Trial
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.