ECE2020 Audio ePoster Presentations General Endocrinology (17 abstracts)
Expanding the clinical and genetic spectrum of 17α-Hydroxylase/17,20-Lyase deficiency: 7 cases and 5 novel mutations in the CYP17A1 gene
Min Sun 1,2 , Jonathan Müller 1,2 , Lorna Gilligan 1,2 , Angela Taylor 1,2 , Fozia Shaheen 1,2 , Tim Cheetham 3 , Louise Denvir 4 , Helena Gleeson 2,5 , Savitha Shenoy 6 , Maria Szarras-Czapnik 7 , Mushtaqur Rahman 8 , Norman Taylor 9 , Guy T’sjoen 10 , Cedric Shackleton 1,2 , Wiebke Arlt 1,2 & Jan Idkowiak 1,2,11
1University of Birmingham, Institute of Metabolism and Systems Research, Birmingham, United Kingdom; 2University of Birmingham, Centre for Endocrinology, Diabetes and Metabolism, Birmingham, United Kingdom; 3Royal Victoria Infirmary, Department of Paediatric Endocrinology, Newcastle Upon Tyne, United Kingdom; 4Queen’s Medical Centre, Department of Paediatric Endocrinology and Diabetes, Notingham, United Kingdom; 5University Hospitals Birmingham NHS Foundation Trust, Department of Endocrinology, Birmingham, United Kingdom; 6University Hospitals of Leicester NHS Trust, Children’s and Adolescent Services, Leceister, United Kingdom; 7The Children’s Memorial Health Institute, Department of Biochemistry and Experimental Medicine, Warsaw, Poland; 8Northwick Park Hospital, Department of Endocrinology, London, United Kingdom; 9King’s College Hospital, Department of Clinical Biochemistry, London, United Kingdom; 10University of Ghent, Department of Endocrinology, Ghent, Belgium; 11Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Department of Endocrinology and Diabetes, Birmingham, United Kingdom
Context: Cytochrome P450 (CYP) 17A1 is located at major branch points of steroidogenesis exerting two distinct catalytic activities: 17α-hydroxylase generates glucocorticoid precursors and 17,20-lyase generates the principal sex steroid precursor dehydroepiandrosterone (DHEA). CYP17A1 deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. In severe 17OHD, affected individuals typically present with both glucocorticoid and sex steroid deficiency and mineralocorticoid excess due to accumulation of steroid precursors. Partial enzyme defects have been rarely reported.
Aims and objectives: To analyse the genetic and phenotypicspectrum of seven patients with 17OHD.
Methods: Urinary steroid profiling (GC-MS), sequencing analysis of the CYP17A1 gene, in silico analysis utilising the crystallized human CYP17A1 protein structure (PDB: 3RUK), in vitro analysis employing a HEK293 cell CYP17A1 overexpression assay with quantification of steroid conversion by LC-MS/MS.
Patients and results: The clinical spectrum ranged from neonatal adrenal insufficiency with failure to thrive and conjugated jaundice toisolated sex steroid deficiency with normal blood pressure and normal serum cortisol after ACTH stimulation. We found five novel (p.Pro409Leu, p.Gly111Val, p.Ala398Glu, p.Ile371Thr and p.Tyr60IlefsLys88X), and three previously described CYP17A1 sequence variants (p.Arg347His, p.Gly436Arg, p.Phe53/54del). In vitro functional analysis showed correlation of 17α-hydroxylase activity with the severity of the phenotype: the missense variants p.Ile371Thr, p.Ala398Glu and p.Arg347His, carried by patients with normal cortisol response, retained up to 14% of residual 17α-hydroxylase activity. The known variant p.Phe53/54del, found in two siblings with a moderate phenotype, retained 5.8% of WT activity. The sequence variants p.Pro409Leu, p.Gly111Val, p.Gly436Arg and p.Tyr60IlefsLys88X, carried by severely affected patients, had <1% residual 17α-hydroxylase activity. In contrast, 17,20-lyase activity was nearly abolished in all variants studied, except for p.Ile371Thr, which retained 3.6% of WT activity. A diagnostic ratio of urinary mineralocorticoid to glucocorticoid metabolites, reflecting 17α-hydroxylase activity, correlated well with both the in vitro17α-hydroxylase activity and the severity of the clinical phenotype. In silicomutant protein analysis identified conformational changes rather than disruption of co-factor binding for all variants studied.
Conclusion: Our findings expand the genetic and clinical spectrum of 17OHD. We describe novel phenotypes at both extremes of the spectrum, with severe neonatal adrenal insufficiency on the one hand, and isolated sex steroid deficiency with normal cortisol response to stimulation on the other. Importantly, attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling in all cases, thus providing a powerful tool for the biochemical diagnosis of 17OHD.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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