Howard, S;
Oleari, R;
Poliandri, A;
Chantzara, V;
Fantin, A;
Ruiz-Babot, G;
Metherell, L;
... Dunkel, L; + view all
(2018)
HS6ST1 insufficiency causes self-limited delayed puberty in contrast with other GnRH deficiency genes.
Journal of Clinical Endocrinology and Metabolism
, 103
(9)
pp. 3420-3429.
10.1210/jc.2018-00646.
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Abstract
Context: Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH which segregate with the trait of familial self-limited DP have not yet been identified. Objective: To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, patients and setting We performed whole exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results: A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (p= 3.01 x 10-5). Biochemical analysis showed that this mutation reduced sulphotransferase activity in vitro. Hs6st1 mRNA was expressed in peri-pubertal wild type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/- and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/- mice despite normal postnatal growth. Conclusions: We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.
| Type: | Article |
|---|---|
| Title: | HS6ST1 insufficiency causes self-limited delayed puberty in contrast with other GnRH deficiency genes |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1210/jc.2018-00646 |
| Publisher version: | https://doi.org/10.1210/jc.2018-00646 |
| Language: | English |
| Additional information: | This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10050791 |
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