Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Janne Tornberg, Gerasimos P. Sykiotis, Kimberly Keefe, Lacey Plummer, Xuan Hoang, Janet E. Hall, Richard Quinton, Stephanie B. Seminara, Virginia Hughes, Guy Van Vliet, Stan Van Uum, William F. Crowley, Hiroko Habuchi, Koji Kimata, Nelly Pitteloud, Hannes E. Bülow

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin- releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.

Original languageEnglish (US)
Pages (from-to)11524-11529
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number28
DOIs
StatePublished - Jul 12 2011

Keywords

  • Heparan sulfotransferase
  • Kallmann syndrome

ASJC Scopus subject areas

  • General

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    Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., & Bülow, H. E. (2011). 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, 108(28), 11524-11529. https://doi.org/10.1073/pnas.1102284108