SFEBES2015 Oral Communications Advances in reproduction and signalling (6 abstracts)
Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism
Sasha Howard 1 , Ariel Poliandri 1 , Helen Storr 1 , Louise Metherell 1 , Claudia Cabrera 2, , Michael Barnes 2, , Helen Warren 3, , Karoliina Wehkalampi 5 , Leo Guasti 1 & Leo Dunkel 1
1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; 4NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK; 5Children’s Hospital, Helsinki University Hospital, Helsinki, Finland; 6University of Helsinki, Helsinki, Finland.
Background: Self-limited delayed puberty (DP) often segregates in an autosomal dominant pattern, suggesting that inheritance is conferred by a small number of genes. However, the underlying genetic background is mostly unknown. By comparison, many genes have been identified where loss-of-function mutations lead to hypogonadotropic hypogonadism (HH). Despite likely overlap between the pathophysiology of delayed puberty and conditions of GnRH deficiency, few studies have examined the contribution of mutations in HH genes to the phenotype of DP.
Methods: We performed whole exome sequencing in 111 members of 18 families from our patient cohort with DP. We filtered the results, seeking potentially pathogenic mutations, with a list of 25 genes identified in the published literature as causal in HH. After follow-up targeted re-sequencing in a further 42 families (288 individuals), one candidate gene was identified. Developmental tissue expression studies and assessment of the enzymatic function of the mutant protein were carried out.
Results: A rare variant in HS6ST1 (Heparan sulfate 6-O sulphotransferase 1) was identified, present in six affected members of one family and not present in 145 controls. No other pathogenic variants in HH genes were identified. HS6ST1 codes for an extracellular matrix component critical for normal neural branching. It is thought to be required for the function of FGFR1 and KAL1 in vivo, both of which are vital for GnRH neuronal development and normal hypothalamic–pituitary–gonadal axis function. The novel variant was predicted to lie within a highly conserved coiled-coil domain and displayed reduced sulphotransferase activity in vitro.
Conclusions: Mutations in HS6ST1 contribute to the phenotype of DP. However, although mutations in genes controlling GnRH neuronal migration and differentiation may cause both HH and DP, the overlap in the genetic basis for the two conditions appears from our study to date to be limited to a subset of HH genes.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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