Alternative titles; symbols
HGNC Approved Gene Symbol: NDST1
Cytogenetic location: 5q33.1 Genomic coordinates (GRCh38): 5:150,497,779-150,558,211 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.1 | Intellectual developmental disorder, autosomal recessive 46 | 616116 | Autosomal recessive | 3 |
NDST1 belongs to a family of bifunctional enzymes involved in heparan sulfate biosynthesis (Aikawa et al., 2001).
Dixon et al. (1995) cloned a human heparan sulfate N-deacetylase/N-sulfotransferase cDNA from a placenta library using a cosmid from the Treacher Collins syndrome (154500) candidate region on chromosome 5q32-q33.1. They detected 2 different mRNAs that vary in the length of their 3-prime untranslated regions but encode the same protein. The sequence predicts an 882-amino acid protein that is 98% identical to the rat protein (Hashimoto et al., 1992).
Aikawa et al. (2001) cloned mouse Ndst1, which encodes a deduced 872-amino acid protein. RT-PCR detected variable Ndst1 expression in all adult mouse tissues examined and in whole mouse embryos at all developmental stages examined.
Gladwin et al. (1996) determined that the HSST gene contains 14 exons.
The Treacher Collins Syndrome Collaborative Group (1996) stated that the most 5-prime exon of the HSST gene lies approximately 150 kb distal to TREACLE (606847), the gene responsible for Treacher Collins syndrome, on chromosome 5q32-q33.1.
Using N-acetylheparosan purified from E. coli capsular polysaccharide as substrate, Aikawa et al. (2001) found that recombinant mouse Ndst enzymes showed distinct ratios of N-acetylglucosamine N-deacetylase to N-sulfotransferase activities. Ndst1 had higher sulfotransferase activity than deacetylation activity against this substrate.
Heparan sulfate is modified by N- and O-sulfation and epimerization. Using RT-PCR, Holmborn et al. (2004) found that Ndst1 and Ndst2 (603268) are the major sulfotransferases expressed in mouse embryonic fibroblasts (MEFs). Ndst1 -/- and Ndst2 -/- double-knockdown MEFs synthesized heparan sulfate that completely lacked N-sulfation and showed reduced, but not eliminated, O-sulfation.
Aikawa et al. (2001) determined that 3 gene duplication events likely occurred to give rise to the 4 vertebrate NDST genes. They proposed that after the initial gene duplication event, a duplication produced NDST1 and NDST2 (603268), followed by a much later duplication that produced NDST3 (603950) and NDST4 (615039).
Intellectual Developmental Disorder, Autosomal Recessive 46
In 8 patients from 4 unrelated families with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified 4 different homozygous missense mutations in the NDST1 gene (600853.0001-600853.0004). Functional studies of the variants were not performed, but all mutations occurred at highly conserved residues in the sulfotransferase domain and were predicted to change the substrate-binding domain and/or to disrupt the 3-dimensional structure of the enzyme. Two of the families had previously been reported to have mutations in the NDST1 gene by homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families with intellectual disability (Najmabadi et al., 2011).
Exclusion Studies
Gladwin et al. (1996) excluded mutations within the coding sequence and adjacent splice junctions of HSST from a causative role in the pathogenesis of Treacher Collins syndrome.
Fan et al. (2000) found that Ndst1-null mice developed respiratory distress and atelectasis that subsequently caused neonatal death. Morphologic examination revealed type II pneumocyte immaturity, which was characterized by an increased glycogen content and a reduced number of lamellar bodies and microvilli. Biochemical analysis indicated that both total phospholipids and desaturated phosphatidylcholine were reduced in the mutant lung.
Reuter et al. (2014) found that knockdown of the Ndst1 ortholog sfl in Drosophila resulted in decreased learning indices in a courtship-conditioning paradigm assay, compared to wildtype. Although brain morphology and locomotion of the mutant flies appeared normal, the altered learning behavior was consistent with impaired long-term memory.
Zhang et al. (2014) developed a line of mice, called Ndst1(ECKO), with Ndst1 knockout in endothelial cells (ECs) only. Homozygous Ndst1(ECKO) mice thrived and reproduced normally but developed central congenital diaphragmatic hernia (CDH; 142340) with variable penetrance, which was preceded by disturbed embryonic development of the diaphragm. Embryonic Ndst1(ECKO) diaphragm showed multiple vascular defects and weakened and disorganized central tendon. Ndst1(ECKO) endothelial cells showed poor motility and proliferation, leading to hypoxia and poor proliferation and survival of diaphragmatic tenocytes. Zhang et al. (2014) observed that the phenotype of Ndst1(ECKO) mice was similar to that of mice lacking expression of the neuronal and endothelial cell guidance molecule Slit3 (603745). Knockout of Slit3, or haploinsufficiency of its cell surface receptor Robo4 (607528), significantly increased CDH penetrance in Ndst1(ECKO) mice. Slit3-induced angiogenesis was strong in wildtype ECs, but was greatly diminished in both Robo4 -/- and Ndst1(ECKO) mice. Heparan sulfate in Ndst1(ECKO) diaphragmatic ECs showed significant reduction in N- and O-sulfation and reduced cell surface Slit3 binding. Zhang et al. (2014) determined that heparan sulfate bound Slit3 but not Robo4. They concluded that CDH in Ndst1(ECKO) mice was caused by defective diaphragm vascular development, and that heparan sulfate in the extracellular matrix facilitates angiogenesis via Slit3-Robo4 signaling.
In 3 sibs, born of consanguineous Iranian parents, with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified a homozygous c.2126G-A transition in the NDST1 gene, resulting in an arg709-to-gln (R709Q) substitution at a highly conserved residue in the sulfotransferase domain. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in ethnically matched controls. Functional studies of the variant were not performed. This family (8600277) had previously been reported by Najmabadi et al. (2011).
In 2 sibs, born of consanguineous Iranian parents, with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified a homozygous c.1926G-T transversion in the NDST1 gene, resulting in a glu642-to-asp (E642D) substitution at a highly conserved residue in the substrate-binding site in the sulfotransferase domain. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in ethnically matched controls. Functional studies of the variant were not performed. This family (M161) had previously been reported by Najmabadi et al. (2011).
In a girl, born of consanguineous Turkish parents (family ER44462), with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified a homozygous c.1918T-C transition in the NDST1 gene, resulting in a phe640-to-leu (F640L) substitution at a highly conserved residue in the substrate-binding site in the sulfotransferase domain. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in ethnically matched controls. Functional studies of the variant were not performed.
In 2 Turkish sibs (family MZ-778/12) with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified a homozygous c.1831G-A transition in the NDST1 gene, resulting in a gly611-to-ser (G611S) substitution at a highly conserved residue near the 3-prime-phosphoadenosine 5-prime-phosphate (PAP)-binding site in the sulfotransferase domain. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in ethnically matched controls. Functional studies of the variant were not performed.
Aikawa, J., Grobe, K., Tsujimoto, M., Esko, J. D. Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase: structure and activity of the fourth member, NDST4. J. Biol. Chem. 276: 5876-5882, 2001. [PubMed: 11087757] [Full Text: https://doi.org/10.1074/jbc.M009606200]
Dixon, J., Loftus, S. K., Gladwin, A. J., Scambler, P. J., Wasmuth, J. J., Dixon, M. J. Cloning of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene from the Treacher Collins syndrome candidate region at 5q32-q33.1. Genomics 26: 239-244, 1995. [PubMed: 7601448] [Full Text: https://doi.org/10.1016/0888-7543(95)80206-2]
Fan, G., Xiao, L., Cheng, L., Wang, X., Sun, B., Hu, G. Targeted disruption of NDST-1 gene leads to pulmonary hypoplasia and neonatal respiratory distress in mice. FEBS Lett. 467: 7-11, 2000. [PubMed: 10664446] [Full Text: https://doi.org/10.1016/s0014-5793(00)01111-x]
Gladwin, A. J., Dixon, J., Loftus, S. K., Wasmuth, J. J., Dixon, M. J. Genomic organization of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene: exclusion from a causative role in the pathogenesis of Treacher Collins syndrome. Genomics 32: 471-473, 1996. [PubMed: 8838814] [Full Text: https://doi.org/10.1006/geno.1996.0145]
Hashimoto, Y., Orellana, A., Gil, G., Hirschberg, C. B. Molecular cloning and expression of rat liver N-heparan sulfate sulfotransferase. J. Biol. Chem. 267: 15744-15750, 1992. [PubMed: 1379236]
Holmborn, K., Ledin, J., Smeds, E., Eriksson, I., Kusche-Gullberg, M., Kjellen, L. Heparan sulfate synthesized by mouse embryonic stem cells deficient in NDST1 and NDST2 is 6-O-sulfated but contains no N-sulfate groups. J. Biol. Chem. 279: 42355-42358, 2004. [PubMed: 15319440] [Full Text: https://doi.org/10.1074/jbc.C400373200]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Reuter, M. S., Musante, L., Hu, H., Diederich, S., Sticht, H., Ekici, A. B., Uebe, S., Wienker, T. F., Bartsch, O., Zechner, U., Oppitz, C., Keleman, K., Jamra, R. A., Najmabadi, H., Schweiger, S., Reis, A., Kahrizi, K. NDST1 missense mutations in autosomal recessive intellectual disability. Am. J. Med. Genet. 164A: 2753-2763, 2014. [PubMed: 25125150] [Full Text: https://doi.org/10.1002/ajmg.a.36723]
Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nature Genet. 12: 130-136, 1996. [PubMed: 8563749] [Full Text: https://doi.org/10.1038/ng0296-130]
Zhang, B., Xiao, W., Qiu, H., Zhang, F., Moniz, H. A., Jaworski, A., Condac, E., Gutierrez-Sanchez, G., Heiss, C., Clugston, R. D., Azadi, P., Greer, J. J., Bergmann, C., Moremen, K. W., Li, D., Linhardt, R. J., Esko, J. D., Wang, L. Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J. Clin. Invest. 124: 209-221, 2014. [PubMed: 24355925] [Full Text: https://doi.org/10.1172/JCI71090]