A New Homozygous Frameshift Mutation in the HSD3B2 Gene in an Apparently Nonconsanguineous Italian Family

作者：Bizzarri Carla; Massimi Arianna; Federici Luca; Cualbu Antonio; Loche Sandro; Bellincampi Lorenza; Bernardini Sergio; Cappa Marco; Porzio Ottavia^*

来源：Hormone Research in Paediatrics, 2016, 86(1): 53-61.

DOI：10.1159/000444712

• Congenital adrenal hyperplasia
• 3 beta-Hydroxysteroid dehydrogenase mutations
• Frameshift HSD3B2 mutation
• Classical congenital adrenal hyperplasia

Background: 3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia (CAH) caused by inactivating mutations in the HSD3B2 gene. Patient and Methods: We report the molecular and structural analysis of the HSD3B2 gene in a 46, XY child born to apparently nonconsanguineous parents and presenting ambiguous genitalia and salt wasting. The steroid profile showed elevated concentrations of 17-hydroxyprogesterone, androstenedione, ACTH and plasma renin, but normal values of cortisol and dehydroepiandrosterone sulfate. Unexpectedly, plasma aldosterone was high. For structural and functional analyses, the three-dimensional structure of 3 beta-HSD2 was modeled using the crystal structure of the short-chain dehydrogenase Gox2253 from Gluconobacter oxydans as a template. Results: The direct DNA sequence of the child revealed a new homozygous frameshift mutation in exon 4 of the HSD3B2 gene, a single nucleotide deletion at codon 319 [GTC(Val) -> GC], yielding premature stop codon in position 367. Molecular homology modeling and secondary structure predictions suggested that the variant sequence might both alter the substrate-binding cleft and compromise the overall stability of the enzyme. Conclusion: We have described the first HSD3B2 gene mutation in the Italian population and analyzed its effect in the context of the 3 beta-HSD2 structure and function.

• 出版日期2016