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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 28 Pg. 11524-9 (Jul 12 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21700882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ANOS1 protein, human
• Caenorhabditis elegans Proteins
• EGL-15 protein, C elegans
• Egl-17 protein, C elegans
• Extracellular Matrix Proteins
• Intercellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Receptors, Fibroblast Growth Factor
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• Sulfotransferases
• heparan sulfate 6-O-sulfotransferase

Topics

• Adult
• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Caenorhabditis elegans (genetics, metabolism)
• Caenorhabditis elegans Proteins (genetics, metabolism)
• Child
• Extracellular Matrix Proteins (genetics, metabolism)
• Female
• Genes, Helminth
• Humans
• Hypogonadism (enzymology, genetics)
• In Vitro Techniques
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Kallmann Syndrome (enzymology, genetics)
• Male
• Middle Aged
• Models, Molecular
• Molecular Sequence Data
• Mutation
• Mutation, Missense
• Nerve Tissue Proteins (genetics, metabolism)
• Pedigree
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, metabolism)
• Receptors, Fibroblast Growth Factor (genetics, metabolism)
• Sequence Homology, Amino Acid
• Species Specificity
• Sulfotransferases (chemistry, deficiency, genetics, metabolism)