The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external Show more
The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation. Minigenes were used to validate the functional effect of mutations in both genes. We evaluated the c.277 + 2 T > G mutation in HSD17B3, and the c.544 G > A, c.548-44 T > G and c.278delG mutations in SRD5A2. We demonstrated that these mutations altered the splicing pattern of these genes. In a genomic era these results illustrate, and remind us, that sequence variants within exon-intron boundaries, which are primarily identified for diagnostic purposes and have unknown pathogenicity, need to be assessed with regards to their impact not only on protein expression, but also on mRNA splicing. Show less
The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46 Show more
The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio < 0.8. In three of the patients, diagnosis was only determined due to the presence of signs of virilization at puberty. All patients had been raised as females, and female gender identity was maintained in all of them. Compound heterozygosis for c.277+2T>G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively. Show less