{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:08:09Z","timestamp":1791198489271,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"28","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,7,12]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>HS 6-O-sulfotransferase 1<\/jats:italic>\n                    (\n                    <jats:italic>HS6ST1<\/jats:italic>\n                    ) 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\n                    <jats:italic>HS6ST1<\/jats:italic>\n                    mutations display reduced activity in vitro and in vivo, suggesting that\n                    <jats:italic>HS6ST1<\/jats:italic>\n                    and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including\n                    <jats:italic>kal-1<\/jats:italic>\n                    , the FGF receptor, and\n                    <jats:italic>FGF<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1102284108","type":"journal-article","created":{"date-parts":[[2011,6,23]],"date-time":"2011-06-23T23:17:04Z","timestamp":1308871024000},"page":"11524-11529","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":157,"title":["<i>Heparan sulfate 6-O-sulfotransferase 1<\/i>\n                    , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism"],"prefix":"10.1073","volume":"108","author":[{"given":"Janne","family":"Tornberg","sequence":"first","affiliation":[{"name":"Department of Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos P.","family":"Sykiotis","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Keefe","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Hoang","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet E.","family":"Hall","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Quinton","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Institute for Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B.","family":"Seminara","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Hughes","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Van Vliet","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Sainte-Justine, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada H3T 1C5;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stan","family":"Van Uum","sequence":"additional","affiliation":[{"name":"Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada N6A 4V2; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William F.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Habuchi","sequence":"additional","affiliation":[{"name":"Research Complex for the Medicine Frontiers, Aichi Medical University, Yazako, Nagakute Aichi 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kimata","sequence":"additional","affiliation":[{"name":"Research Complex for the Medicine Frontiers, Aichi Medical University, Yazako, Nagakute Aichi 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Pitteloud","sequence":"additional","affiliation":[{"name":"Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes E.","family":"B\u00fclow","sequence":"additional","affiliation":[{"name":"Department of Genetics, and"},{"name":"Dominick P. 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