Alternative titles; symbols
HGNC Approved Gene Symbol: HS6ST1
Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38) : 2:128,265,480-128,318,868 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.3 | {Hypogonadotropic hypogonadism 15 with or without anosmia} | 614880 | Autosomal dominant | 3 |
Heparan sulfate (HS) 6-O-sulfotransferase catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate (Habuchi et al., 1998).
By screening a human fetal brain cDNA library with a Chinese hamster Hs6st cDNA, Habuchi et al. (1998) isolated human HS6ST cDNAs. The predicted 401-amino acid human HS6ST protein is a type II transmembrane protein, with an N-terminal transmembrane domain. A putative cleavage site occurs near the C-terminal end of the transmembrane domain. HS6ST contains 2 potential N-glycosylation sites. It does not share significant sequence similarity to other known sulfotransferases, including HS2ST. HS6ST does not contain a conserved 3-prime-phosphoadenosine 5-prime-phosphosulfate-binding site sequence, or a 'P-loop,' which is found in most sulfotransferases and has been implicated as an ATP- or GTP-binding site. Northern blot analysis of human fetal brain RNA detected a 3.9-kb HS6ST transcript.
Habuchi et al. (2000) cloned Hs6st1 from a mouse brain cDNA library. The deduced 401-amino acid protein has characteristics of a type II transmembrane protein, with a short N-terminal segment followed by a hydrophobic sequence. It also contains 2 N-glycosylation sites. Northern blot analysis detected a 3.9-kb Hs6st1 transcript in most mouse tissues examined, with predominant expression in liver.
The International Radiation Hybrid Mapping Consortium mapped the HS6ST1 gene to chromosome 2 (RH78052).
Habuchi et al. (1998) found that recombinant HS6ST expressed in mammalian cells exhibited HS6ST activity.
Habuchi et al. (2000) demonstrated elevated 6-O-sulfotransferase activity in the cytoplasm of COS-7 cells transfected with mouse Hs6st1. Hs6st1 was also secreted into the medium. Hs6st1 showed 6-O-sulfotransferase activity against HS, N-sulfated heparosan, heparin, and some HS derivatives. It did not show sulfotransferase activity toward other glycosaminoglycans examined.
In experiments in C. elegans, Tornberg et al. (2011) observed that HS cell-specifically regulates neural branching in vivo in concert with other genes that are associated with hypogonadotropic hypogonadism (see 147950), including KAL1 (300836), FGF8 (600483), and FGFR1 (136350). The findings were consistent with a model in which KAL1 acts as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.
In 7 probands with hypogonadotropic hypogonadism with or without anosmia (HH15; 614880), Tornberg et al. (2011) identified 5 heterozygous missense mutations (604846.0001-604846.0005). All of the HS6ST1 variants affected highly conserved residues, exhibited reduced activity compared to wildtype, and were not found in 500 controls or the SNP database. Because clinical variability was evident both within and across families carrying the same genetic variant, Tornberg et al. (2011) analyzed 8 additional HH-associated genes to test whether other genetic factors were contributing to the observed variability, and identified heterozygous variants in the FGFR1 gene (136350.0025) and in the NELF gene (608137.0001) in 2 of the HH families, respectively. The authors concluded that the identified HS6ST1 missense mutations might not be sufficient to cause disease, and suggested that HS6ST1 represents an important gene contributing pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction.
In the HH family in which Tornberg et al. (2011) had identified mutations in both the HS6ST1 (604846.0002) and FGFR1 (136350.0025) genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified additional mutations in 2 more genes, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
In 1 female and 2 male probands from 3 unrelated families with hypogonadotropic hypogonadism (HH15; 614880), 1 with anosmia and 2 with a normal sense of smell, Tornberg et al. (2011) identified heterozygosity for a 1114C-T transition in the HS6ST1 gene, resulting in an arg372-to-trp (R372W) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 25 to 35% reduction in enzymatic activity with the R372W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R372W mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. The female HH proband had absent puberty whereas the 2 male probands had partial puberty, and 1 male patient, who was anosmic, had osteoporosis, whereas the other male patient had osteopenia. In addition, the female proband had a brother with delayed puberty who did not carry the HS6ST1 R372W mutation, whereas the anosmic male proband had an unaffected brother who did carry the mutation. Analysis of 8 known HH-associated genes in these families revealed that the anosmic male proband carried an additional heterozygous missense mutation in the NELF gene (608137.0001); no other mutations were identified. Tornberg et al. (2011) concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction.
Lek et al. (2016) noted that this variant has a high allele frequency (0.0123) in the South Asian population in the ExAC database and that the database also reports 4 homozygotes for the variant.
In a 55-year-old woman with hypogonadotropic hypogonadism with anosmia (HH15; 614880) from a large French Canadian pedigree with several consanguineous loops, previously reported by White et al. (1983) and in which affected individuals displayed variable phenotypes, Tornberg et al. (2011) identified homozygosity for an 886C-T transition in the HS6ST1 gene, resulting in an arg296-to-trp (R296W) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 50% reduction in enzymatic activity with the R296W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296W mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. Additional features in the proband included bilateral genu valgus and osteoporosis with multiple vertebral and tibial fractures. The proband's brother, who also had anosmic HH, was heterozygous for the R296W mutation, as was their unaffected father and 3 other family members, including 1 with anosmic HH, 1 with anosmic HH and cleft palate, and 1 unaffected individual. Other phenotypes among untested family members included normosmic HH in 1 individual and isolated cleft palate in 3. Analysis of 8 known HH-associated genes revealed that the proband, her brother, and their unaffected father all carried an additional heterozygous missense mutation in the FGFR1 gene (R250Q; 136350.0025), as did 2 other family members, 1 with anosmic HH and 1 with anosmic HH and cleft palate. The FGFR1 mutation was also found in heterozygosity in an unaffected family member who did not carry the R296W HS6ST1 mutation. No mutations were identified in the other HH-associated genes. Tornberg et al. (2011) concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction.
In the French Canadian pedigree in which Tornberg et al. (2011) had identified mutations in both the FGFR1 and HS6ST1 genes, Miraoui et al. (2013) identified additional mutations in 2 FGF-network genes, FGF17 (I108T; 603725.0001) and FLRT3 (E97G, 604808.0001 and S144I, 604808.0002).
In a 10.5-year-old boy with anosmic hypogonadotropic hypogonadism (HH15; 614880), born of consanguineous parents, Tornberg et al. (2011) identified heterozygosity for an 887G-A transition in the HS6ST1 gene, resulting in an arg296-to-gln (R296Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 15 to 30% reduction in enzymatic activity with the R296Q mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296Q mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI at 11 months of age revealed a normal hypothalamic area and small pituitary, although the olfactory bulbs and nerves could not be assessed. The proband's mother, who had only delayed puberty and a normal sense of smell, was also heterozygous for the mutation. Tornberg et al. (2011) proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction.
In a 30-year-old man who was born with anosmic hypogonadotropic hypogonadism (HH15; 614880), cleft palate, and bilateral genu valgus, Tornberg et al. (2011) identified heterozygosity for a 938G-A transition in the HS6ST1 gene, resulting in an arg313-to-gln (R313Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 30% reduction in enzymatic activity with the R313Q mutant compared to wildtype when HS was the acceptor substrate, whereas mutant activity was similar to wildtype when completely desulfated re-N-sulfated heparin was used as the substrate. In an in vivo assay involving C. elegans, the R313Q mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI in the proband showed absent olfactory bulbs and a normal pituitary. The proband's father, who had only delayed puberty, and an asymptomatic, fertile sister were both also heterozygous for the mutation, whereas another sister with anosmia did not carry the mutation. In addition, the paternal grandmother had delayed puberty, and the paternal grandfather was anosmic. Tornberg et al. (2011) proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for human reproduction.
In a 36-year-old man who had anosmic hypogonadotropic hypogonadism (HH15; 614880), Tornberg et al. (2011) identified heterozygosity for a 1180A-G transition in the HS6ST1 gene, resulting in a met394-to-val (M394V) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 30 to 70% reduction in enzymatic activity with the M394V mutant compared to wildtype, and in an in vivo assay involving C. elegans, the M394V mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. At 21 years of age, the proband presented for failure to undergo puberty. He was overweight and eunuchoidal, with Tanner II pubic hair and small testes, and had severe bilateral genu valgus. While the patient was on replacement testosterone therapy, his wife conceived. Later, he was found to have a normal adult serum testosterone level and normal sperm count after having discontinued his replacement therapy, indicating reversal of his GnRH-deficiency HH. Fourteen years later, repeat neuroendocrine evaluation confirmed a sustained reversal of his GnRH deficiency; MRI scan showed absent olfactory bulbs and a small pituitary gland.
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White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am. J. Med. Genet. 15: 417-435, 1983. [PubMed: 6881209] [Full Text: https://doi.org/10.1002/ajmg.1320150307]