Partial deficiency of 17alpha-hydroxylase/17,20-lyase caused by a novel missense mutation in the canonical cytochrome heme-interacting motif.
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Rubtsov P, Nizhnik A, Dedov I, Kalinchenko N, Petrov V, Orekhova A, Spirin P, Prassolov V, Tiulpakov A
Partial deficiency of 17alpha-hydroxylase/17,20-lyase caused by a novel missense mutation in the canonical cytochrome heme-interacting motif.
Eur J Endocrinol. 2015 May;172(5):K19-25. doi: 10.1530/EJE-14-0834. Epub 2015 Feb 3.
- PubMed ID
- 25650406 [ View in PubMed]
- Abstract
BACKGROUND: Deficiency of 17alpha-hydroxylase/17,20-lyase is a rare cause of 46,XY disordered sex development. OBJECTIVE: We characterize in vitro and in vivo effects of two novel CYP17A1 gene mutations identified in a patient with a mild phenotype of CYP17A1 deficiency. SUBJECTS AND METHODS: A 46,XY patient presented with ambiguous genitalia. CYP17A1 deficiency was suspected at 2 months on the basis of steroid analysis performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mutational analysis of the CYP17A1 gene was performed by PCR and Sanger sequencing. To characterize the effect of CYP17A1 mutation on 17alpha-hydroxylase and 17,20-lyase activities in vitro, HEK293 cells were transiently transfected with CYP17A1 expression plasmids, incubated with progesterone or 17-OH-pregnenolone and concentrations of 17-OH-progesterone or DHEA were then measured in the cell culture medium by LC-MS/MS. RESULTS: Clinical and hormonal findings in the patient were consistent with partial combined deficiency of 17alpha-hydroxylase/17,20-lyase. The sequencing of the CYP17A1 gene in the patient revealed compound heterozygosity for two novel mutations: c.107delT p.R36fsX107 and p.W121R. After 6-h in vitro culture of transfected HEK293 cells in the presence of 1 muM progesterone, 17alpha-hydroxylase activity of p.W121R mutant was 60.5+/-16.3%, while 17,20-lyase activity of mutant measured from the amount of DHEA produced in the presence of 1 muM of 17-OH-pregnenolone was 15.8+/-2.6% compared with the WT. CONCLUSIONS: p.W121R substitution, affecting the first residue in the conserved heme-interacting WXXXR motif of CYP17A1, is associated with partial combined deficiency of 17alpha-hydroxylase/17,20-lyase.