Intellectual disabilityGene: NUS1
Comment on mode of inheritance: Only single family with a biallelic pattern is reported so assigning only monoallelic inheritance until more evidence is gathered for biallelic inheritance.
Created: 28 Feb 2019, 10:33 a.m.
Comment on list classification: Following review by the Genomics England clinical team it was decided to rate this gene red on the Intellectual disabilities panel at this time.
Further cases advised to confirm MOI and delineate potential ID phenotype aside from that associated with an epileptic encephalopathy.
It will be added as Amber to the Genetic epilepsy syndromes panel.
Created: 28 Feb 2019, 10:27 a.m.
NUS1 is associated with Mental retardation, autosomal dominant 55, with seizures (AD inheritance) and ?Congenital disorder of glycosylation, type 1aa (AR inheritance) in OMIM. It is associated with Epilepsy and intellectual disability in Gene2Phenotype (probable) with monoallelic inheritance.
PMID: 25066056 (Park et al 2014) - 2 sibs, born of unrelated Czech parents of Roma descent, with congenital disorder of glycosylation type Iaa - a homozygous missense mutation in the NUS1 gene (p.Arg290His (R290H), which is located in the evolutionarily conserved C-terminal domain of NgBR) . The siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. Functional studies with WT and mutant fibroblasts show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR.
PMID: 29100083 (Hamdan et al 2017) - performed whole-genome sequencing (WGS) on 197 developmental and epileptic encephalopathy individuals and their unaffected parents. 3 unrelated individuals identified with de novo changes in NUS1 - p.Asp248Alafs), p.Val48Profs)∗7, exon 2 deletion. All had seizures and mild to severe ID.
Created: 14 Feb 2019, 2:02 p.m.
Please consider upgrading this gene (NUS1 is also rated Green in the epilepsy panel).
Den et al (2019 - PMID: 31656175) reported on 2 additional unrelated individuals (aged 17 and 59y) both presenting intellectual disability, epilepsy , involuntary movements, ataxia and scoliosis. Both were found to harbor the same splicing variant in NUS1 (NM_138459.4:c.691+1C>A) following exome sequencing. Using lymphoblastoid cell lines from both individuals it was demonstrated that the variant creates a new splice donor site in exon 3 further creating a new reading frame and producing a premature termination codon [c.601_691del or p.(Arg202Glnfs*9)]. Using cyclohexamide, it was further shown that the mutant mRNA is partially subjected to NMD. [Additional variants identified by exome for the 2 subjects were non diagnostic (/VUS). An SPTAN1 nonsense variant identified in one was inherited from an unaffected parent (dominant-negative mechanism listed in G2P for this gene / in ClinVar all pLoF variants are submitted as VUS)].
Created: 12 Jan 2020, 6:22 p.m. | Last Modified: 12 Jan 2020, 6:22 p.m.
Panel Version: 3.0
Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals.
NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding).
As a result, NUS1 can be considered for inclusion in the ID panel probably as amber.
Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] :
Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation.
The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis.
Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders).
Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR).
In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants.
Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures].
Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject).
The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG.
Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated.
Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants.
Phenotypes of all 27 individuals are provided in Dataset_S04. Cognitive impairment (apparently PD-related and not corresponding to ID) was listed among the non-motor features for 3 of 27 subjects (all with missense variants).
NUS1 has been found to be differentially expressed in PD mouse models.
RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain.
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 15 Jan 2019, 12:29 p.m.
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
#617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance for gene: NUS1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: nus1 has been classified as Red List (Low Evidence).
gene: NUS1 was added gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Penetrance for gene: NUS1 were set to unknown Review for gene: NUS1 was set to AMBER gene: NUS1 was marked as current diagnostic