A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

Abstract

X‐linked intellectual disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized. We used whole exome sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G > C (G306R) in the X‐linked heparan sulfate 6‐O‐sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulfate from adenosine 3′‐phosphate, 5′‐phosphosulfate to the sixth position of the N‐sulphoglucosamine residue in heparan sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site, and its effect was considered “deleterious” by in‐silico tools. An in‐vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…The last XLID update published, estimated that 141 genes are associated with XLID. Since then, more genes have been associated to XLID such as CXorf56 , HS6ST2 , NAA15 , POLA1 and SLC9A7 (Figure ). However, the link of some of these genes to XLID is still questionable .…”

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

“…Inf). Genes in Group IV included those coding for two core proteins ( GPC2 90-92 and GPC5 93-95 ), three NDSTs ( NDST2 96-98 , NDST3 99-101 , and NDST4 102,103 ), two HS6STs ( HS6ST2 104,105 , HS6ST3 106,107 ), all HS3STs ( HS3ST1 108-110 , HS3ST2 111,112 , HS3ST3A1 113-115 , HS3ST3B1 115 , HS3ST4 116 , HS3ST5 117 , and HS3ST6 118,119 ), and one HS levels regulating genes (EXTL1 120 ). Based in current available data and literature records, it appeared that, at least in the absence of instigating stimuli, these genes are non-causative of disease and are not essential for normal development and homeostasis (Supp.…”

Cerebellar Morphology and Behavioral Profiles in Mice Lacking Heparan Sulfate Ndst Gene Function

“…Therefore, together with these reports, our findings indicate the possibility that fully sulfated HS in cell types that express Cre under L7 promotor control plays a previously unsuspected role in the regulation of female reproductive behavior. Further support for essential HS functions in normal brain physiology comes from the observations that Ndst1 is a candidate gene for autosomal recessive intellectual disability in four unrelated families [ 64 , 65 ], that the Drosophila Ndst orthologue Sulfateless plays a role in normal social interactions and repetitive behavior in the fly [ 66 ], that Glypican 4 associates with hyperactivity and social interaction deficits in mice [ 67 ], and that a HS 6-O sulfotransferase gene variant associates with intellectual disability in humans [ 68 ].…”