Alternative titles; symbols
HGNC Approved Gene Symbol: NUS1
Cytogenetic location: 6q22.1 Genomic coordinates (GRCh38) : 6:117,675,469-117,710,727 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.1 | ?Congenital disorder of glycosylation, type 1aa | 617082 | Autosomal recessive | 3 |
| Intellectual developmental disorder, autosomal dominant 55, with seizures | 617831 | Autosomal dominant | 3 |
The NUS1 gene encodes a membrane protein that is a subunit of cis-prenyltransferase (cis-PTase) and is involved in the synthesis of dolichol, which is necessary for protein glycosylation (summary by Park et al., 2014).
Miao et al. (2006) found that the N-terminal domain of NOGOB (604475) induced chemotaxis in human umbilical vein endothelial cells (HUVECs). By screening a heart cDNAs expression library for genes that supported chemotaxis following transfection in COS or CHO cells, followed by database analysis, Miao et al. (2006) identified NGBR. The deduced 293-amino acid protein has an N-terminal signal peptide, a putative ectodomain, a type-1A transmembrane domain, and a long C-terminal cytoplasmic domain. Western blot analysis detected high Ngbr expression in mouse heart, liver, kidney, and pancreas.
Harrison et al. (2011) stated that human NGBR has 3 N-terminal transmembrane domains and a C-terminal domain that shares significant similarity with cis-isoprenyltransferase (CIT, or DHDDS; 608172). Glycosidase treatment revealed that the C-terminal domain of NGBR was N-glycosylated. NGBR localized to ER membranes in 2 conformations, a minor form in which the C-terminal domain faced the lumen, and a major form in which the C-terminal domain faced the cytoplasm.
By genomic sequence analysis, Miao et al. (2006) mapped the NUS1 gene to chromosome 6q22.31.
Miao et al. (2006) found that NOGOB and NGBR colocalized during angiogenesis induced by VEGF (192240) and wound healing in vivo. NOGOB and NGBR mediated chemotaxis in HUVECs and induced tube formation in 3-dimensional cultures.
By yeast 2-hybrid screening of a human heart cDNA expression library, Harrison et al. (2009) found that NGBR interacted with the cholesterol-binding protein NPC2 (601015), which is essential for intracellular trafficking of LDL-derived cholesterol. The majority of NPC2 localized to lysosomes at steady state, but the C-terminal domain of NGBR interacted with nascent NPC2 in the ER lumen and stabilized NPC2 against proteasomal degradation. Knockdown of NGBR in human cell lines or knockout of Ngbr in mouse embryonic fibroblasts reduced NPC2 content, leading to increased intracellular cholesterol accumulation and loss of sterol sensing.
Harrison et al. (2011) found that, when facing the ER lumen, the C-terminal domain of NGBR interacted with NPC2. However, when the C-terminal domain was oriented toward the cytosol, NGBR interacted with and stabilized CIT. Knockdown of NGBR in human endothelial/epithelial hybridomas dramatically reduced the content of lipid-linked oligosaccharides, total free glycan pools, and protein N-glycosylation, and it reduced microsomal CIT activity. Reciprocal coimmunoprecipitation analysis revealed that epitope-tagged NGBR and CIT interacted via the C-terminal domain of NGBR. Overexpression and knockdown studies revealed that NGBR and CIT stabilized each other.
In yeast, Park et al. (2014) demonstrated that NoRB is a subunit of a heteromeric cis-PTase required for dolichol synthesis. It interacts with DHDDS.
Congenital Disorder of Glycosylation type Iaa
In 2 sibs, born of unrelated Czech parents of Roma descent, with congenital disorder of glycosylation type Iaa (CDG1AA; 617082), Park et al. (2014) identified a homozygous missense mutation in the NUS1 gene (R290H; 610463.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed hypoglycosylation of LAMP1 (153330) and ICAM1 (147840), and studies of patient cells and yeast were consistent with impaired NUS1 function.
Autosomal Dominant Intellectual Developmental Disorder 55 with Seizures
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Hamdan et al. (2017) identified 3 different de novo heterozygous mutations in the NUS1 gene (610463.0002-610463.0004). Two of the mutations were truncating, and 1 was an intragenic deletion encompassing all of exon 2. Two patients were found by whole-genome sequencing of 197 individuals with developmental epileptic encephalopathy; the third patient was found by clinical exome sequencing from another patient cohort. Studies of the variants and studies of patients cells were not performed, but Hamdan et al. (2017) postulated haploinsufficiency as the pathogenic mechanism.
In 3 patients with MRD55 with seizures, Yu et al. (2021) identified de novo heterozygous mutations in the NUS1 gene (610463.0004-610463.0007) by whole-exome sequencing.
Park et al. (2014) found that complete knockdown of the Nus1 gene in mice was embryonic lethal before E6.5, indicating postimplantation lethality. Mouse embryonic fibroblasts with conditional knockdown of the Nus1 allele showed accumulation of free cholesterol, decreased cis-PTase activity, and decreased mannose incorporation into protein. Mutant fibroblasts showed decreased viability in response to treatment with an HMG-CoA reductase inhibitor compared to controls. In addition, the cells showed activation of the unfolded protein response pathway of ER stress.
Yu et al. (2021) developed a zebrafish morpholino knockdown for the nus1 gene. At 4-5 days postfertilization (dpf), the fish morphants demonstrated abnormal swimming, including short bursts of high-speed swim events compared to wildtype fish. Npc2 (601015) protein expression was decreased in morphant embryos at 1-4 dpf, and abnormal cholesterol accumulation, particularly in hindbrain, spinal cord and neurons, was seen by filipin staining. Decreased Lamp1 (153330) proteolysis was also seen in the morphant fish, indicating impaired lysosomal degradation. Treatment of the fish with 2-hydroxypropyl-beta-cyclodextrin to facilitate cholesterol efflux from lysosomes resulted in improved swimming parameters, reduced cholesterol storage, and improved lysosomal function.
In 2 sibs, born of unrelated Czech parents of Roma descent, with congenital disorder of glycosylation type Iaa (CDG1AA; 617082), Park et al. (2014) identified a homozygous c.869G-A transition (c.869G-A, NM_138459) in the NUS1 gene, resulting in an arg290-to-his (R290H) substitution at a residue in the highly conserved C-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in an in-house database of over 250 exomes. It was found in the heterozygous state in 2 of 255 individuals of Roma origin. Patient fibroblasts showed normal expression of the mutant protein, but mutant cells showed increased accumulation of free cholesterol similar to cells in which NUS1 was silenced. In addition, cis-PTase activity and mannose incorporation into proteins was markedly decreased in patient fibroblasts compared to controls.
In an 8-year-old boy (indvKW) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Hamdan et al. (2017) identified a de novo heterozygous 1-bp deletion (c.743delA, NM_138459.4) in the NUS1 gene, predicted to result in a frameshift and premature termination (Asp248AlasfsTer4) in the cis-IPTase domain. The mutation was found by clinical exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency.
In a 15-year-old boy (HSJ0623) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Hamdan et al. (2017) identified a de novo heterozygous 14-bp duplication (c.128_141dup, NM_138459.4) in the NUS1 gene, predicted to result in a frameshift and premature termination (Val48ProfsTer7) in transmembrane 2. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the 1000 Genomes Project, Exome Variant Server, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency.
In a 29-year-old woman (HSJ0627) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Hamdan et al. (2017) identified a de novo heterozygous 1.30-kb deletion in the NUS1 gene encompassing the entire exon 2 (NM_138459.4), which encodes transmembrane 3. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the 1000 Genomes Project, Exome Variant Server, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency.
In a 14-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Yu et al. (2021) identified a de novo heterozygous c.734G-T transversion in the NUS1 gene, resulting in a gly245-to-val (G245V) substitution. The mutation was identified by whole-exome sequencing. Examination of patient fibroblasts showed reduction in NGBR protein as well as in NUS1 transcript levels. Lipid analysis of patient fibroblasts demonstrated reduced total polyprenol and dolichol lipids. Steady-state NPC2 (601015) levels were decreased in patient fibroblasts, and the cells had increased lysosomal cholesterol as determined by filipin staining. Analysis of lysosomal enzymes showed reduced acid-beta-glucosidase and beta-hexosaminidase activity, demonstrating multiple lysosomal defects. Overexpression of NUS1 with the G245V mutation in HeLa cells did not show abnormalities in cholesterol storage or NGBR expression, providing evidence that the G245V mutation has a loss-of-function mechanism of pathogenicity.
In a 35-year-old woman (patient 2) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Yu et al. (2021) identified a de novo heterozygous c.752T-G transversion in the NUS1 gene, resulting in a leu251-to-ter (L251X) substitution. The mutation was identified by whole-exome sequencing. Western blot analysis in patient fibroblasts showed a reduction in full-length NGBR protein as well the presence of a lower molecular weight band, indicating a likely truncated NGBR protein. NUS1 transcript levels were not reduced in patient fibroblasts; however, gel-based analysis of transcripts demonstrated shorter species indicating that aberrant mRNA may be degraded by nonsense-mediated decay. Lipid analysis of the patient fibroblasts demonstrated reduced total polyprenol and dolichol lipids. Steady-state NPC2 (601015) levels were decreased in patient fibroblasts, and the cells had increased lysosomal cholesterol as determined by filipin staining. Analysis of lysosomal enzymes showed reduced acid-beta-glucosidase and beta-hexosaminidase activity, demonstrating multiple lysosomal defects.
In a 5-year-old boy (patient 3) with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55; 617831), Yu et al. (2021) identified a de novo heterozygous c.451+1G-A mutation in the NUS1 gene. The mutation was found by whole-exome sequencing. Functional studies were not performed.
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., and 95 others. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 101: 664-685, 2017. [PubMed: 29100083] [Full Text: https://doi.org/10.1016/j.ajhg.2017.09.008]
Harrison, K. D., Miao, R. Q., Fernandez-Hernando, C., Suarez, Y., Davalos, A., Sessa, W. C. Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking. Cell Metab. 10: 208-218, 2009. [PubMed: 19723497] [Full Text: https://doi.org/10.1016/j.cmet.2009.07.003]
Harrison, K. D., Park, E. J., Gao, N., Kuo, A., Rush, J. S., Waechter, C. J., Lehrman, M. A., Sessa, W. C. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 30: 2490-2500, 2011. [PubMed: 21572394] [Full Text: https://doi.org/10.1038/emboj.2011.147]
Miao, R. Q., Gao, Y., Harrison, K. D., Prendergast, J., Acevedo, L. M., Yu, J., Hu, F., Strittmatter, S. M., Sessa, W. C. Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proc. Nat. Acad. Sci. 103: 10997-11002, 2006. [PubMed: 16835300] [Full Text: https://doi.org/10.1073/pnas.0602427103]
Park, E. J., Grabinska, K. A., Guan, Z., Stranecky, V., Hartmannova, H., Hodanova, K., Baresova, V., Sovova, J., Jozsef, L., Ondruskova, N., Hansikova, H., Honzik, T., Zeman, J., Hulkova, H., Wen, R., Kmoch, S., Sessa, W. C. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 20: 448-457, 2014. [PubMed: 25066056] [Full Text: https://doi.org/10.1016/j.cmet.2014.06.016]
Yu, S.-H., Wang, T., Wiggins, K., Louie, R. J., Merino, E. F., Skinner, C., Cassera, M. B., Meagher, K. M., Goldberg, P., Rismanchi, N., Chen, D., Lyons, M. J., Flanagan-Street, H., Street, R. Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency. Genet. Med. 23: 1305-1314, 2021. [PubMed: 33731878] [Full Text: https://doi.org/10.1038/s41436-021-01137-6]