NUS1

Gene Facts

3
Haplo
Score
0
Triplo
Score

Gene Facts External Data Attribution

HGNC Symbol

NUS1 (HGNC:21042) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar

HGNC Name

NUS1 dehydrodolichyl diphosphate synthase subunit

Gene type

protein-coding gene

Locus type

gene with protein product

Previous symbols

C6orf68

Alias symbols

MGC7199, NgBR, TANGO14

%HI

pLI

1(Read more about gnomAD pLI score)

LOEUF

Cytoband

6q22.1

Genomic Coordinates

GRCh37/hg19:	chr6:117996632-118031890	NCBI Ensembl UCSC
GRCh38/hg38:	chr6:117675469-117710727	NCBI Ensembl UCSC

MANE Select Transcript

NM_138459.5 ENST00000368494.4 (Read more about MANE Select)

Function

With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery (PubMed:21572394, PubMed:25066056, PubMed:28842490, PubMed:32817466, PubMed:33077723). 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 ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:

ISCA-26528

ClinGen Curation ID:

CCID:007585

Curation Status:

Complete

Issue Type:

Dosage Curation - Gene

Haploinsufficiency:

Sufficient Evidence for Haploinsufficiency (3)

Read full report...

Triplosensitivity:

No Evidence for Triplosensitivity (0)

Read full report...

Last Evaluated:

09/27/2022

Haploinsufficiency (HI) Score Details

HI Score:

HI Evidence Strength:

Sufficient Evidence for Haploinsufficiency (Disclaimer)

HI Disease:

Complex Neurodevelopmental Disorder Monarch

HI Evidence:

PUBMED: 29100083
Hamdan et al. (2017) performed whole-genome sequencing (WGS) in 197 individuals with unexplained developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. They identified three de novo loss of function variants in NUS1. These included a frameshift variant in exon 1 (c.128_141dup [p.Val48Profs∗7]), an approximately 1.3 kb deletion encompassing the entire exon 2 and a truncating variant (c.743delA [p.Asp248Alafs∗4]). The patients all presented with global developmental delay (or isolated motor delay) which eventually evolved into mild to severe intellectual disability. They all presented with generalized myoclonic seizures (with myoclonic status epilepticus in one individual and with myoclonic absences in two individuals). All individuals showed other generalized seizure types, including atonic seizures (drop attacks) or generalized tonic-clonic seizures. EEG revealed either generalized epileptic activity or bi-frontal epileptic discharges. Movement disorders, including tremor (in two individuals) and ataxia (in one individual) were also described.
PUBMED: 34532305
Zhang et al. (2021) report a de novo frameshift variant (c.51_54delTCTG, p.L18Tfs*31) in a Chinese patient with intellectual disability and epileptic seizures.
PUBMED: 33731878
Yu et al. (2021) describe a female patient with a de novo heterozygous c.752T>G (p.Leu251*) variant. The patient had a history of moderate intellectual disability, seizures, tremor and slight gait ataxia. They also describe a patient with a de novo heterozygous c.415+1G>A variant with a a history of developmental delay, seizures, and tremor. The authors showed functional evidence in that patient fibroblasts exhibit a spectrum of lysosomal defects, most clearly manifested by lower abundance of the lysosomal cholesterol efflux protein, NPC2, and accumulation of free cholesterol in this organelle. Using zebrafish they showed a comparable reduction in nus1 expression is sufficient to cause similar movement phenotypes that correlate with cholesterol accumulation in the brain and neuromuscular system.
PUBMED: 31656175
Den et al (2019) reported two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis with the same, de novo splice site variant (c.691 + 1C > A) found by WGS. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay.

HI Evidence Comments:

Individuals with de novo, heterozygous, loss-of-function variants in NUS1 have been reported in association with autosomal dominant intellectual disability with seizures. NUS1 is also a proposed contributor to Parkinson’s disease, as an increased frequency of missense variants within this gene have been observed in patients with early onset Parkinson’s disease (Guo et al (2018) PMID: 30348779). NUS1 variants are also associated with autosomal recessive congenital disorder of glycosylation type Iaa (OMIM # 617082). Additional evidence: PMID:24824130 Szafranski et al. (2015) identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. The 6q22.1 microdeletions centered on a 250 kb critical region that includes only NUS1 and the promoter of SLC35F1.

Triplosensitivity (TS) Score Details

TS Score:

TS Evidence Strength:

No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000006.11)

Send Feedback

', empty: [ '

Nothing found.

' ],/*, header: [ '

' ],*/ suggestion: function (data) { return '

' + data.label + ' ' + data.alias + ' ' + data.hgnc + '' + (data.curated ? 'Curated ' : '') + '

' } }, limit: 20, minLength: 3, highlight: true, hint: false, autoselect:true, }).bind('typeahead:selected',function(evt,item){ window.location = item.url; }); $('.queryGeneName').typeahead(null, { name: 'termGeneName', display: 'label', source: termGeneName, templates: { //header: '

Header

', //footer: '

Disease has been curated by ClinGen