Alternative titles; symbols
HGNC Approved Gene Symbol: NANS
SNOMEDCT: 773303005;
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38) : 9:98,056,732-98,083,077 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.33 | Spondyloepimetaphyseal dysplasia, Genevieve type | 610442 | Autosomal recessive | 3 |
The sialic acids are a family of 9-carbon 2-keto-3-deoxy sugars. They are frequently the terminal sugars on secreted and cell surface glycoproteins and glycolipids. Sialic acids participate in many important biologic recognition events (summary by Lawrence et al., 2000).
By searching a human EST database for sequences that are homologous to the E. coli sialic acid synthase gene neuB, Lawrence et al. (2000) identified SAS. They isolated a full-length human SAS coding sequence. The deduced 359-amino acid SAS protein shares approximately 36% amino acid sequence identity with the E. coli neuB protein. Expression of the SAS gene in an E. coli neuB-negative mutant resulted in partial restoration of sialic acid synthase activity. In insect cells, expression of SAS caused N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN) production. In vitro, SAS used N-acetylmannosamine 6-phosphate and mannose-6-phosphate as substrates to generate phosphorylated forms of Neu5Ac and KDN, respectively; however, it exhibited much higher activity toward the Neu5Ac phosphate product. Northern blot analysis detected an approximately 1.3-kb SAS transcript in all human tissues examined.
In 9 patients from 6 families with infantile-onset severe developmental delay and the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442), van Karnebeek et al. (2016) identified biallelic mutations in the NANS gene (605202.0001-605202.0008). Patient body fluids showed elevated N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins.
Using morpholino oligonucleotides (MO) to knock down nansa, 1 of 2 zebrafish orthologs for the human NANS gene, Van Karnebeek et al. (2016) observed embryos with small heads, pericardial edema, and developmental anomalies of the skeleton at 6 days postfertilization. The morphants showed a complex phenotype in the area of the head, including hypoplastic or absent Meckel cartilage; lack of basihyal cartilage; shortened and abnormal ethmoid plate, trabecula, parachordal and palatoquadrate; and absent certaobranchial structures. Addition of sialic acid to the zebrafish embryo water immediately after MO injection resulted in partial rescue of the skeletal phenotype; adding sialic acid 24 hours postfertilization had no effect, suggesting that sialic acid has a critical role in early embryonic development. MO knockdown of the other NANS zebrafish ortholog, nansb, did not cause an overtly abnormal phenotype.
In 2 Italian sisters with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442), originally reported by Camera et al. (1993), van Karnebeek et al. (2016) identified compound heterozygosity for a deletion/insertion mutation (c.449-10_449-5delGATTACinsATGG, NM_018946.3) in intron 3 of the NANS gene, and a 1-bp insertion (c.389_390insT; 605202.0002). In addition, a brother and sister with SEMDG from another Italian family were compound heterozygous for the same deletion/insertion and a splice site mutation (c.448+1G-A; 605202.0003). The 3 mutations segregated with disease in both families. Haplotype reconstruction using exome data revealed a 1.38-Mb shared region on chromosome 9 in the 4 patients, indicative of a common origin of the insertion/deletion. Analysis of patient mRNA demonstrated that both the insertion/deletion and the splice site mutation resulted in aberrant splicing of exons 3 and 4; both variants were also present in the ExAC database (November 2015), at frequencies of 0.00004947 and 0.00002633, respectively. The 1-bp insertion, which was present in the Wellderly database (January 2016) at a frequency of 0.0008, was predicted to result in a premature termination codon (Lys131GlnfsTer8) and was shown to trigger nonsense-mediated decay. Analysis of NANS enzyme activity in patient fibroblasts showed reduced production of sialic acid compared to controls; fibroblasts from a heterozygous parent showed an intermediate level of NANS activity.
For discussion of the 1-bp insertion (c.389_390insT, NM_018946.3) in exon 3 of the NANS gene, predicted to result in a premature termination codon (Lys131GlnfsTer8), that was found in compound heterozygous state in 2 Italian sisters with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442) by van Karnebeek et al. (2016), see 605202.0001.
For discussion of the splice site mutation (c.448+1G-A, NM_018946.3) in intron 3 of the NANS gene that was found in compound heterozygous state in 2 Italian sibs with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442) by van Karnebeek et al. (2016), see 605202.0001.
In an 11-year-old Pakistani girl with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442), originally reported by Genevieve et al. (2005), van Karnebeek et al. (2016) identified homozygosity for a c.452G-A transition (c.452G-A, NM_018946.3) in exon 4 of the NANS gene, resulting in an arg151-to-his (R151H) substitution. The mutation, which segregated with disease in the family, was found in the Wellderly database (January 2016) at a frequency of 0.0008. The proband had a similarly affected sister from whom DNA was unavailable.
In a Japanese sister and brother with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442), van Karnebeek et al. (2016) identified compound heterozygosity for a missense mutation and an in-frame insertion in the NANS gene: the first was a c.398G-T (c.398G-T, NM_018946.3) transversion in exon 3, resulting in a gly133-to-val (G133V) substitution near the active site, and the second was a 3-bp insertion (c.981insATC; 605202.0006) in exon 6, resulting in duplication of ile327.
For discussion of the 3-bp insertion (c.981insATC, NM_018946.3) in exon 6 of the NANS gene, resulting in duplication of ile327, that was found in compound heterozygous state in 2 Japanese sibs with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442) by van Karnebeek et al. (2016), see 605202.0005.
In a 4-year-old Dutch boy with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442), van Karnebeek et al. (2016) identified compound heterozygosity for missense mutations in the NANS gene: the first was a c.562T-C transition (c.562T-C, NM_018946.3) in exon 4, resulting in a tyr188-to-his (Y188H) substitution in the active site, and the second was a c.709C-T transition in exon 4, resulting in an arg237-to-cys (R237C; 605202.0008) substitution at the dimer interface. The mutation segregated with disease in the family and was not found in the ExAC (November 2015) or Wellderly (January 2016) databases. Analysis of NANS enzyme activity in patient fibroblasts showed reduced production of sialic acid compared to controls.
For discussion of the c.709C-T transition (c.709C-T, NM_018946.3) in exon 4 of the NANS gene, resulting in an arg237-to-cys (R237C) substitution, that was found in compound heterozygous state in a Dutch boy with the Genevieve type of spondyloepimetaphyseal dysplasia (SEMDG; 610442) by van Karnebeek et al. (2016), see 605202.0007.
Camera, G., Camera, A., Gatti, R. Sponastrime dysplasia: report on two siblings with mental retardation. Pediat. Radiol. 23: 611-614, 1993. [PubMed: 8152878] [Full Text: https://doi.org/10.1007/BF02014981]
Genevieve, D., Heron, D., El Ghouzzi, V., Prost-Squarcioni, C., Le Merrer, M., Jacquette, A., Sanlaville, D., Pinton, F., Villeneuve, N., Kalifa, G., Munnich, A., Cormier-Daire, V. Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation. Europ. J. Hum. Genet. 13: 541-546, 2005. [PubMed: 15726110] [Full Text: https://doi.org/10.1038/sj.ejhg.5201339]
Lawrence, S. M., Huddleston, K. A., Pitts, L. R., Nguyen, N., Lee, Y. C., Vann, W. F., Coleman, T. A., Betenbaugh, M. J. Cloning and expression of the human N-acetylneuraminic acid phosphate synthase gene with 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid biosynthetic ability. J. Biol. Chem. 275: 17869-17877, 2000. [PubMed: 10749855] [Full Text: https://doi.org/10.1074/jbc.M000217200]
van Karnebeek, C. D. M., Bonafe, L., Wen, X.-Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., Ashikov, A., Garavelli, L., Mammi, I., Turolla, L., Breen, C., Donnai, D., and 34 others. NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genet. 48: 777-784, 2016. Note: Erratum: Nature Genet. 49: 969 only, 2017. [PubMed: 27213289] [Full Text: https://doi.org/10.1038/ng.3578]