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.
Subject(s)
Hypogonadism/enzymology , Hypogonadism/genetics , Mutation , Sulfotransferases/genetics , Adult , Amino Acid Sequence , Amino Acid Substitution , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Child , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Female , Genes, Helminth , Humans , In Vitro Techniques , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Kallmann Syndrome/enzymology , Kallmann Syndrome/genetics , Male , Middle Aged , Models, Molecular , Molecular Sequence Data , Mutation, Missense , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Pedigree , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Sequence Homology, Amino Acid , Species Specificity , Sulfotransferases/chemistry , Sulfotransferases/deficiency , Sulfotransferases/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: Kallmann's syndrome (KS) is characterized by hypogonadotrophic hypogonadism in association with anosmia or hyposmia. This entity can be associated with X-linked ichthyosis (XLI) in a contiguous gene syndrome. Genetic defects have been demonstrated on the Xp22.3 region explaining the presence of one or both entities in affected individuals. In this report we describe the molecular findings in four patients, pertaining to a three generation family, with KS which was associated with XLI in two of them. MEASUREMENTS: Enzymatic activity of steroid sulphatase was measured in leucocytes. Polymerase chain reaction of the 14 exons of the Kallmann gene (KAL) and of the 5' and 3' extremes of the steroid sulphatase gene was performed in genomic DNA. PCR products of the 14 exons of the KAL gene were purified and sequenced. RESULTS: Absence of steroid sulphatase activity and a complete deletion of the STS gene were demonstrated in both patients with XLI. In all subjects, the 14 KAL gene exons amplified in a normal fashion; no mutation was documented after sequencing all exons. CONCLUSIONS: Although it has been proposed recently that the X-linked form of the disease accounts for the minority of patients with Kallman's syndrome, the pedigree chart of this family demonstrates this inheritance pattern. Various possibilities are mentioned in order to explain the absence of mutation in the KAL gene. The coexistence, in this family, of Kallman's syndrome individuals and patients with Kallman's syndrome and X-linked ichthyosis is discussed.
Subject(s)
Ichthyosis, X-Linked/genetics , Kallmann Syndrome/genetics , Adult , Arylsulfatases/genetics , Arylsulfatases/metabolism , Child , Exons , Female , Gene Deletion , Humans , Ichthyosis, X-Linked/complications , Ichthyosis, X-Linked/enzymology , Kallmann Syndrome/complications , Kallmann Syndrome/enzymology , Leukocytes/enzymology , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Steryl-SulfataseABSTRACT
Ten of 31 patients with steroid sulphatase (STS) deficiency were found to have an allergic disease (bronchial asthma, allergic rhinitis, or atopic dermatitis). STS deficiency may predispose patients to allergic disease.
