A New Homozygous Frameshift Mutation in the <b><i>HSD3B2</i></b> Gene in an Apparently Nonconsanguineous Italian Family

Abstract

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.

Genetic testing of XY newborns with a suspected disorder of sex development

“…Disorders of androgen synthesis include luteinizing hormone receptor defects and defects in the testicular steroidogenesis pathway ( Table 2) Among all forms of 46, XY DSD, the genetic causes are clear for those presenting with enzyme deficiencies of 'classic' androgen biosynthesis pathways, including 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) or 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2) deficiency. Whilst the deficit of 17β-HSD3 may interfere only with androgen production and more often is detected because of virilization at puberty, 3β-HSD2 may affect all steroidogenic pathways and, therefore, results in severe salt-wasting and non-salt wasting forms of CAH and ambiguous genitalia in affected boys [106,107]. Over 45 causative mutations have been reported in HSD17B3 and the prevalence has been reported about 1 per 150 000 [108].…”

Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency

“…We synthetized the studies published according to the mentioned methodology in Table 1 [ 5 , 22 , 25 , 26 , 27 , 31 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”

Genetic Heterogeneity in Adrenal Insufficiency

“…The enzyme 3βHSD2 is encoded by gene HSD3β2, which is located on chromosome 1. Mutations are mainly represented by missense and nonsense mutations, whereas deletions and insertions are less frequent (Bizzarri et al 2016). These mutations mainly affect protein stability, leading to complete or nearly complete enzyme inactivity.…”

“…These mutations mainly affect protein stability, leading to complete or nearly complete enzyme inactivity. However, different mutations, including 956delT, affecting substratebinding region (Simard et al 2005;Bizzarri et al 2016), and uniparental isodisomy of chromosome 1, have been rarely reported (Panzer et al 2017).…”