Open AccessHeparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism
Author(s) -
Janne Tornberg,
Gerasimos P. Sykiotis,
Kimberly W. Keefe,
Lacey Plummer,
Xuan Lan Thi 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
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1102284108
Subject(s) - heparan sulfate , fibroblast growth factor , biology , microbiology and biotechnology , extracellular , hypogonadotropic hypogonadism , extracellular matrix , medicine , endocrinology , receptor , genetics , cell , hormone
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 inHS 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-associatedHS6ST1 mutations display reduced activity in vitro and in vivo, suggesting thatHS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments inCaenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, includingkal-1 , the FGF receptor, andFGF . 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.