BSPED2015 Poster Presentations (1) (7 abstracts)
Mutations in HS6ST1 cause self-limited delayed puberty (DP) in addition to idiopathic hypogonadotropic hypogonadism (IHH)
Sasha Howard 1 , Ariel Poliandre 1 , Helen L Storr 1 , Louise A Metherell 1 , Claudia Cabrera 2 , Helen Warren 3 , Michael Barnes 2 , Karoliina Wehkalampi 4 , Leonardo 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; 4Children’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Background: Self-limited DP often segregates in an autosomal dominant pattern, but in the majority of patients the neuroendocrine pathophysiology and its genetic regulation remain unclear. By comparison, many genes have been identified where loss-of-function mutations lead to IHH. Despite likely overlap between the pathophysiology of DP and conditions of GnRH deficiency, few studies have examined the contribution of mutations in IHH 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 IHH. 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 performed.
Results: A rare variant in HS6ST1 (Heparan sulfate 6-O sulphotransferase i) was identified, present in six affected members in one family and not present in 145 controls. No other pathogenic variants in IHH genes were identified. HS6ST1 codes for an enzyme that modifies extracellular matrix components 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. Our variant is predicted to lie within a highly conserved coiled-coil domain and displays reduced sulphotransferase activity in vitro.
Conclusions: Mutations in HS6ST1 contribute to the phenotype of both IHH and DP. Thus, it appears that misregulation of GnRH neuronal migration and differentiation may cause both IHH and DP. However, the overlap in the genetic basis for these two conditions appears from our study to date to be limited to a subset of IHH genes.
Volume 39
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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