NUS1

protein-coding

NUS1 dehydrodolichyl diphosphate synthase subunit, the group of Dehydrodolichyl diphosphate synthase

Gene summary

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. [provided by RefSeq, May 2017]

Previous symbols:

C6orf68

MANE transcript

NM_138459.5

Inheritance

AR, AD

ClinVar variants

P:93U:231B:116

Top phenotype

Intellectual developmental disorder, autosomal dominant, 55, with seizures; Congenital disorder of glycosylation, type 1aa

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr6:117,675,469-117,710,727

External References & Databases

Ensembl (ENSG00000153989)

Transcript & Mutation Effects

hg38 • Region Span ~35.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital disorder of glycosylation, type IaaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014904

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 55, with seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030921

Submitter: G2P

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 55, with seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030921

Submitter: Ambry Genetics

progressive myoclonus epilepsySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020074

Submitter: PanelApp Australia

congenital disorder of glycosylation, type IaaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014904

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 55, with seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030921

Submitter: Labcorp Genetics (formerly Invitae)

congenital disorder of glycosylation, type IaaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014904

Submitter: Labcorp Genetics (formerly Invitae)

progressive myoclonus epilepsyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020074

Submitter: ClinGen

*NUS1* was first reported in relation to autosomal dominant progressive myoclonus epilepsy in 2017 (PMID: 29100083) when Hamdan et al. described three patients with myoclonic seizures, disorders of intellectual development and tremor, or ataxia. This gene encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), and is involved in the synthesis of dolichol, which is necessary for protein glycosylation [It interacts with dehydrodolichyl diphosphate synthase complex subunit (DHDDS) and promotes cis-prenyltransferase (cis-PTase) activity] (PMID: 19723497, PMID: 21572394). Notably, in 2014 (PMID: 25066056) autosomal recessive inheritance of *NUS1* p.R290H variant was linked to the congenital disorder of glycosylation type1Iaa presenting with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit, and visual impairment with discrete bilateral macular lesions. The studies reported in this curation detected patients with heterozygous loss of function variants in *NUS1*, presenting with variable clinical presentations including different seizure types, varying degrees of developmental delay, and the presence of myoclonus or other motor phenotypes. Several non-sense, frameshift, and splice site variants, as well as copy number variations (CNVs) affecting all or part of *NUS1*, are reported in more than 25 probands across 15 publications (PMIDs: 29100083, 3165617, 32485575, 33111323, 32959737, 3453230, 33731878, 33798445, 35949226, 37249665, 38291835, 37470039, 38520610, 39772664, 39934081). Most reported variants are de novo with the exception of the familial c.22_23insA (PMID:32485575), which is segregated in 5 individuals. In summary, there is definitive evidence to support the relationship between *NUS1* and autosomal dominant progressive myoclonus epilepsy. 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 Epilepsy GCEP on the meeting date 05/20/2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant, 55, with seizures; Congenital disorder of glycosylation, type 1aaAD/AR

Manifestation: Biochemical; Neurologic; 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: 25066056; 29100083

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUS1 variants in ClinVar

12 Conditions Cataloged

Congenital disorder of glycosylation, type IaaTotal: 382

not providedTotal: 99

Inborn genetic diseasesTotal: 54

Intellectual developmental disorder, autosomal dominant 55, with seizuresTotal: 49

not specifiedTotal: 32

NUS1-related disorderTotal: 21

NUS1-related neurodevelopmental disorderTotal: 1

Congenital bilateral perisylvian syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138459.5. 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			2 clinvar	103 clinvar	2 clinvar	107
missense	1 clinvar	5 clinvar	225 clinvar	10 clinvar	1 clinvar	242
nonsense	19 clinvar	11 clinvar				30
start loss		2 clinvar	1 clinvar			3
frameshift	31 clinvar	14 clinvar	1 clinvar			46
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	2 clinvar			12
Total	54	39	231	113	3	440

Highest pathogenic variant AF is 0.0000034245636

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138459.5	RefSeq	NP_612468.1	5	MANE Select
ENST00000368494.4	Ensembl	ENSP00000357480.3	5	MANE Select
ENST00000885063.1	Ensembl	ENSP00000555122.1	6	Standard
ENST00000885063.2	Ensembl	ENSP00000555122.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nus1	Danio rerio	Structure: intersegmental vessel Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

nus1

Danio rerio

Structure: intersegmental vessel

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Terpenoid backbone biosynthesis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Synthesis of Dolichyl-phosphate
Synthesis of substrates in N-glycan biosythesis

Biological Process

angiogenesis
dolichyl diphosphate biosynthetic process
dolichol biosynthetic process
cell differentiation
regulation of intracellular cholesterol transport

Molecular Function

prenyltransferase activity
protein binding
dehydrodolichyl diphosphate synthase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
dehydrodolichyl diphosphate synthase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368494
Coding exons: 5
Length: 35139
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.876	126	157	0.803	0.00000760	1875
Missense (PolyPhen)		14	35.938	0.38956		427
Synonymous	-0.136	67	65.6	1.02	0.00000319	577
Loss of Function	3.23	0	12.1	0.00	5.13e-7	150

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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) (PubMed:21572394, PubMed:25066056, PubMed:28842490). 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 (PubMed:16835300). {ECO:0000269|PubMed:16835300, ECO:0000269|PubMed:21572394, ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:25066056}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 55, with seizures (MRD55) [MIM:617831]: A form of mental retardation, 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. {ECO:0000269|PubMed:29100083}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.120

Essentials

Essential (CRISPR): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.160

Gene Damage Prediction

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