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FB2026_01
,
released March 12, 2026
The human NDST genes (NDST1, NDST2, NDST3, and NDST4), a family of enzymes involved in heparan sulfate biosynthesis, have been identified as potential susceptibility loci for autism spectrum disorder (ASD; FBhh0000514). All four are bifunctional heparan sulfate N-deacetylase/N-sulfotransferases (EC 2.8.2.8). NDST1 and 2 are expressed in most human tissues, whereas NDST 3 and 4 are largely brain-specific (https://www.proteinatlas.org/). There is a single high-ranking ortholog in Drosophila for all four human NDST genes, sfl, for which misexpression elements, gene and enhancer traps, loss-of-function alleles, and multiple RNAi targeting lines have been generated. NDST1 has already been implicated in an autosomal recessive form of intellectual disability (FBhh0000248) and potentially in azoospermia (FBhh0000239).
None of the four human NDST genes have been introduced into flies.
In an un-biased GWA analysis using 40 wild-type lines from the DGRP, flies were scored on three behavioral measures analogous to behaviors used to characterize to autism spectrum disorder phenotypes in humans. Lines with variants in the Drosophila gene sfl show abnormal phenotypes for all three behavioral measures: latency to mating during courtship behavior, repetitive grooming behavior, and social spacing. Knocking down sfl in neurons shows the same ASD-associated behaviors, although some effects are sex-specific.
[updated September 2019 by FlyBase; FBrf0222196]
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (MIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from MIM:209850; 2017.03.18]
Autism spectrum disorders are complex, pervasive, and multifactorial neurodevelopmental conditions. Observation of aberrant behavior forms the basis of diagnosis, with criteria focused on impairments in social communication and interaction, and restricted, repetitive patterns of behavior, interests, or activities. (Masi et al. 2017 and references therein, pubmed:28213805.)
The SFARI Gene autism database ( https:gene.sfari.org ) does not list any of the NDST (NDST1-4) genes. [2020.11.05]
Four NDST genes are expressed in mammals, where NDST1 and NDST2 seem to be the major ones, present in most tissues and cells. (Dagälv et al. 2015 and references therein, pubmed:25325954.)
The body of research identifying genetic deletions and duplications, inherited and de novo, and rare and common variants in ASD is expansive. Evidence for genetic variants in the etiology of ASD includes genes involved in intellectual disability and neuropsychiatric disorders, common pathway genes and ASD-risk genes, multigenic contributions from rare or common variations, DNA mutations, and environmental effects on gene expression and/or protein function. Rare genetic risk factors, including those resulting in ASD-related syndromes (e.g. Fragile X), chromosomal abnormalities, and penetrant genes are estimated to contribute to ~20% of ASDs. At least 5% of non-syndromic, idiopathic, and primarily simplex ASD are caused by de novo copy-number variants. It is estimated that 400-1000 genes are likely to lead to a susceptibility to autism. (Masi et al. 2017 and references therein, pubmed:28213805.)
Heparan sulfate (HS) proteoglycans at the surface of cells and in the extracellular matrix interact with growth factors and morphogens, thereby influencing key processes in embryonic development and homeostasis. The HS glycosaminoglycan chains are synthesized in the Golgi compartment, where N-acetylglucosamine (GlcNAc) residues and glucuronic acid residues are added in alternating sequence to a linkage tetrasaccharide attached to specific serine residues in the proteoglycan core protein. While polymerization of the HS chains mainly is carried out by the HS-copolymerase EXT1/EXT2, several enzymes are responsible for their modification. The N-deacetylase/N-sulfotransferases (NDSTs), which remove N-acetyl groups and replace them with sulfate groups, are responsible for the overall design of the HS chain. Subsequent O-sulfation and epimerization of glucuronic to iduronic acid mostly occurs in close proximity to N-sulfoglucosamine residues. (Adapted from Dagälv et al. 2015 and references therein, pubmed:25325954.)
Many to one: 4 human genes to 1 Drosophila gene.
High-ranking ortholog of human NDST1. sfl also shares orthology with three similar paralogs in humans: NDST2, NDST3, and NDST4.