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.heparan sulfotransferase | Kallmann syndrome T he coordinated assembly of the nervous system in metazoans requires the migration of the large majority of neurons from their place of origin to their final destination in the brain (1). These processes require the complex interplay of many factors, including secreted and transmembrane proteins that mediate communication between cells. The activity of such factors is greatly influenced by the extracellular environment (2). For example, heparan sulfates (HSs), a class of molecularly diverse extracellular glycosaminoglycans, have been shown to be crucial for neural development in mice (3). From work in model organisms, it has become clear that much of the function of HS during neural development is embedded within complex modification patterns of the HS sugar residues (reviewed in refs. 4 and 5). HS modification patterns serve specific and instructive functions during neural development and are believed to regulate ligand-receptor interactions (6-8). These patterns arise as the consequence of nonuniform modifications of the sugar moieties, including sulfations, deacetylations, and epimerizations that are introduced by specific HS-modifying enzymes (9) (Fig. 1A). It is unknown whether the function of HS modifications impinges on normal human development and disease susceptibility.Idiopathic hypogonadotropic hypogonadism (IHH) is a clinically and genetically heterogeneous condition that is characterized by lack of sexual maturation and infertility in the absence of other organic etiologies (10). Patients with IHH either have a normal sense of smell [normosmic IHH (nIHH)] or have an impaired sense of smell (anosmia

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

“…Cleft lip and/or palate and skeletal anomalies indicate mutations in genes encoding components of the FGF8 signalling pathway (for example, FGFR1, FGF8 and HS60ST1). 17,20,21,104,153 Signs associated with CHARGE syndrome (CHARGE: coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, and ear anomalies and/or deafness) favour screening for mutations in CHD7. [24][25][26]104 Likewise, the association of CHH with congenital hearing impairment should direct screening towards CHD7, SOX10 and/or IL17RD.…”

Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

“…Mice that grow to adults exhibit aberrant morphology in placental labyrinthine microvessels (11) and lung (11,12) and show erroneous axon navigation in the optic chiasm (13). In humans, Hs6st-1 is mutated in families with idiopathic hypogonadotropic hypogonadism (14). Other organisms, such as zebrafish (15,16), Caenorhabditis elegans (17), Drosophila (18,19), and chick (20), also have abnormal development due to defects in 6-O-sulfation in HS.…”

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

“…(58) realizaram o escrutínio do HS6ST1 em 338 pacientes hipogonádi-cos, encontrando alterações gênicas (seis em heterozigose e uma em homozigose) em cinco casos com sín-drome de Kallmann e dois outros com hipogonadismo hipogonadotrófico normósmico. Todas essas alterações foram localizadas em regiões proteicas altamente conservadas e levavam a uma atividade enzimática reduzida da 6-O-sulfotransferase sulfato de heparina in vitro e in vivo (58). Contudo, num contexto de interação com a proteína anosmina, foram observados diferentes graus de perda de função das proteínas HS6ST1 mutantes, indicando que a 6-O sulfotransferase de sulfato de heparina pode agir tanto por vias dependentes quanto independentes de anosmina-1 (58).…”