HS6ST1 – Kallmann Syndrome

Kallmann syndrome (KS) is a form of congenital hypogonadotropic hypogonadism (MONDO:0018800) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. A recent case report identified a heterozygous HS6ST1 mutation in a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following cessation of long-term androgen therapy (PMID:40724652). HS6ST1 encodes heparan sulfate 6-O-sulfotransferase 1, which fine-tunes extracellular matrix sulfation crucial for FGF-mediated GnRH neuron guidance. The association between HS6ST1 and KS has been substantiated by identification of rare variants in patient cohorts and concordant functional models. This evidence informs diagnostic gene panels and suggests mechanistic targets to enhance endogenous GnRH function.

Genetic screening of KS and idiopathic hypogonadotropic hypogonadism (IHH) cohorts identified heterozygous HS6ST1 missense variants in five unrelated probands with KS (PMID:21700882). All reported variants—c.1144C>T (p.Arg382Trp), c.917G>A (p.Arg306Gln), c.968G>A (p.Arg323Gln), c.1210A>G (p.Met404Val), and c.916C>T (p.Arg306Trp)—affect conserved catalytic residues. These variants occur in a heterozygous state, consistent with autosomal dominant inheritance. Segregation data are limited to single-family observations without extended co-segregation. No recurrent or founder HS6ST1 alleles have been described, and variant prevalence in KS cohorts remains low (<1%).

The HS6ST1 variant spectrum in KS is comprised exclusively of missense substitutions targeting the sulfotransferase domain, with no loss-of-function or splice-site variants reported in KS contexts. All five variants are absent or extremely rare in population databases, supporting pathogenicity. Structural modeling and conservation analyses further implicate disruption of donor-substrate interactions. Deep-intronic or structural HS6ST1 alterations have not been explored in KS.

Functional assays demonstrate that these HS6ST1 mutations impair enzymatic activity. In vitro biochemical studies show significantly reduced sulfotransferase function for p.Arg382Trp and p.Arg306Gln alleles (PMID:21700882). Caenorhabditis elegans models reveal defective neural branching consistent with GnRH neuron migration deficits. Mouse neuronal cell lines with Hs6st1 disruption exhibit transcriptome changes overlapping those of Fgfr1 mutants, indicating convergent pathway dysregulation (PMID:35899427). Drosophila models underscore the necessity of overall heparan sulfate sulfation for effective FGF signaling (PMID:16966419).

Collectively, heterozygous HS6ST1 haploinsufficiency emerges as a mechanism underlying KS. Disrupted extracellular heparan sulfate sulfation impairs FGF-driven GnRH neuron guidance, converging with FGFR1 and CHD7 pathways. The autosomal dominant inheritance suggests dosage sensitivity rather than dominant-negative effects. While genetic evidence is limited by few probands and minimal segregation data, robust functional concordance across in vitro and in vivo models strengthens pathogenic validity. Further family studies and functional rescue experiments would bolster this gene-disease link.

References

• Life (Basel, Switzerland) • 2025 • Spontaneous Improvement of Hypogonadotropic Hypogonadism in a Patient with PCSK1 and HS6ST1 Mutations: A Case Report. PMID:40724652
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. PMID:21700882
• The Journal of Cell Biology • 2006 • Specific and flexible roles of heparan sulfate modifications in Drosophila FGF signaling. PMID:16966419
• Human Molecular Genetics • 2022 • Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1. PMID:35899427

Evidence Based Scoring (AI generated)