HS6ST2(Heparan Sulfate 6-O-Sulfotransferase 2), located on chromosome Xq26.2 (GRCh38: X:132,626,015–132,961,370), encodes a member of the heparan sulfate (HS) 6-O-sulfotransferase family. The enzyme catalyzes the transfer of sulfate from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the 6-O position of N-sulfoglucosamine (GlcNS) residues within heparan sulfate chains. HS6ST2 is primarily expressed in the brain (including basal ganglia), eye, ovary, placenta, kidney, and skeletal muscle. The protein is a type II transmembrane enzyme localized mainly in the Golgi apparatus, where HS biosynthesis and modification occur. It shows sulfotransferase activity toward HS, N-sulfated heparosan, and heparin, but not toward other glycosaminoglycans.
Heparan sulfates are linear polysaccharides widely present on cell surfaces and in the extracellular matrix, typically as part of heparan sulfate proteoglycans (HSPGs). These molecules interact with numerous ligands and regulate key biological processes, including development, cell signaling, angiogenesis, and tissue homeostasis.
Multiple transcript variants of HS6ST2have been described, with tissue-specific expression. A full-length isoform (~605 amino acids) is mainly expressed in the brain and in the developing eye, while a shorter isoform (lacking ~40 amino acids) is expressed in other tissues.
Variants and pathophysiology
Pathogenic or likely pathogenic variants in HS6ST2are associated with Paganini-Miozzo syndrome (MRXSPM), an extremely rare X-linked neurodevelopmental disorder. HS6ST2has also been proposed as a candidate gene in keratoconus, although current evidence for this association remains limited.
The first reported disease-associated variant was the maternally inherited hemizygous missense change c.916G>C (p.Gly306Arg) (c.1036G>C NM_001394073.1) identified in two monozygotic Italian male twins with developmental delay, intellectual disability, severe myopia, and mild dysmorphic features. This variant lies within the HS 6-O-sulfotransferase domain. In silico modeling predicted a deleterious effect on protein conformation, and functional studies in HEK293 cells demonstrated significantly reduced 6-O-sulfotransferase activity, supporting a damaging effect on HS6ST2 function.
A second missense variant, c.979C>T, p.Pro327Ser (c.1099C>T, NM_001394073.1) was reported in a male child with developmental delay, seizures, EEG abnormalities, cerebral white matter changes, and minor facial anomalies. This variant was classified as a variant of uncertain significance; it is predicted to be damaging, but no functional validation has been reported.
A third missense variant, c.764C>A, p.Pro255Gln (c.884C>A, NM_001394073.1), was identified in a Chinese boy with developmental delay, ventriculomegaly, EEG abnormalities, and metabolic/biochemical abnormalities. In silico analyses suggested reduced protein stability, and in vitro studies showed altered HS6ST2 protein expression at the post-transcriptional level, consistent with functional impairment.
In addition, Xu et al. (2023) identified the missense variant c.1589T>C, p.Phe530Ser (c.1709T>C, NM_001394073.1) in HS6ST2in a trio-based whole-exome sequencing study of keratoconus. However, no functional data were provided, and HS6ST2should currently be regarded as a candidate susceptibility gene rather than a confirmed disease gene for keratoconus.
Overall, available evidence supports a disease mechanism involving impaired HS6ST2 function and abnormal heparan sulfate sulfation, likely affecting developmental pathways relevant to the nervous system and eye.
