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

Carla Bizzarri, Arianna Massimi, Luca Federici, Antonio Cualbu, Sandro Loche, Lorenza Bellincampi, Sergio Bernardini, Marco Cappa, Ottavia Porzio

Research output: Contribution to journalArticlepeer-review


Background: 3β-Hydroxysteroid dehydrogenase (3β-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 3β-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 3β-HSD2 structure and function.

Original languageEnglish
Pages (from-to)53-61
Number of pages9
JournalHormone Research in Paediatrics
Issue number1
Publication statusPublished - Aug 1 2016


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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism


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