Karger Publishers, Hormone Research in Paediatrics, 1(86), p. 53-61, 2016
DOI: 10.1159/000444712
Full text: Unavailable
<b><i>Background:</i></b> 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia (CAH) caused by inactivating mutations in the <i>HSD3B2 </i>gene. <b><i>Patient and Methods:</i></b> We report the molecular and structural analysis of the <i>HSD3B2 </i>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 <i>Gluconobacter oxydans</i> as a template. <b><i>Results:</i></b> The direct DNA sequence of the child revealed a new homozygous frameshift mutation in exon 4 of the <i>HSD3B2 </i>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. <b><i>Conclusion:</i></b> We have described the first <i>HSD3B2 </i>gene mutation in the Italian population and analyzed its effect in the context of the 3β-HSD2 structure and function.