HS6ST1 – Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism (HH) is characterized by deficient gonadotropin-releasing hormone (GnRH) secretion leading to absent puberty and infertility (HP:0000826). Heterozygous variants in HS6ST1 (heparan sulfate 6-O-sulfotransferase 1) have been implicated in autosomal-dominant forms of HH with or without anosmia (HP:0000458).

Genetic evidence includes three unrelated probands harboring rare HS6ST1 variants: a 29-year-old man with spontaneous HH recovery carrying a heterozygous HS6ST1 missense change (PMID:40724652), one patient in a cohort of 27 idiopathic congenital HH cases with a likely pathogenic HS6ST1 allele (PMID:33819414), and a pedigree with self-limited delayed puberty showing autosomal-dominant segregation of c.1124G>A (p.Arg375His) in six affected relatives (P = 3.01×10⁻⁵) (PMID:29931354).

Inheritance is autosomal dominant, supported by segregation of c.1124G>A (p.Arg375His) in six affected family members (PMID:29931354). Additional heterozygous HS6ST1 variants, including c.1144C>T (p.Arg382Trp), have been identified in patients with idiopathic HH and Kallmann syndrome, underscoring the spectrum of GnRH deficiency alleles.

Functional assays demonstrate that HS6ST1 IHH-associated variants (e.g., c.1144C>T (p.Arg382Trp)) exhibit markedly reduced sulfotransferase activity in vitro and impair GnRH neuron development in Caenorhabditis elegans models (PMID:21700882). In mice, heterozygous Hs6st1 loss recapitulates delayed vaginal opening despite normal neuronal counts, confirming haploinsufficiency as the pathogenic mechanism (PMID:29931354).

Recent transcriptomic profiling of Hs6st1- and Fgfr1-deficient neuronal cells reveals convergent dysregulation of extracellular matrix and chromatin pathways, implicating coordinated signaling via Sox9/Sox10 and Chd7 in GnRH neuron maturation (PMID:35899427). These studies collectively support a loss-of-function model whereby HS6ST1 variants disrupt 6-O-sulfation of heparan sulfate, impairing GnRH neuronal migration and function.

No reports have conclusively refuted HS6ST1’s role in HH, though oligogenic inheritance and incomplete penetrance suggest the need for comprehensive genetic counseling. Diagnostic HS6ST1 sequencing should be considered in patients with familial or sporadic HH, especially when anosmia or self-limited delayed puberty is present.

Key Take-home: Heterozygous HS6ST1 loss-of-function variants cause autosomal-dominant hypogonadotropic hypogonadism via haploinsufficiency, supporting their inclusion in clinical genetic testing panels.

References

• Spontaneous Improvement of Hypogonadotropic Hypogonadism in a Patient with PCSK1 and HS6ST1 Mutations: A Case Report. Life (Basel, Switzerland) • 2025 • PMID:40724652
• Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism. Journal of Pediatric Endocrinology & Metabolism • 2021 • PMID:33819414
• HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes. The Journal of Clinical Endocrinology and Metabolism • 2018 • PMID:29931354
• Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proceedings of the National Academy of Sciences of the United States of America • 2011 • PMID:21700882
• Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1. Human Molecular Genetics • 2022 • PMID:35899427

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