Substitution Mutation C268Y Causes 17 -Hydroxysteroid Dehydrogenase 3 Deficiency

Abstract

The 17 beta-hydroxysteroid dehydrogenase (HSD) type 3 isozyme catalyzes the conversion of androstenedione to testosterone in the testis. Deleterious mutations in the HSD17B3 gene cause undermasculinization in genetic males attributable to impaired testosterone biosynthesis. Hence, a hallmark of this autosomal recessive disorder is a decreased plasma testosterone-to-androstenedione ratio. Here, a novel C268Y substitution mutation in exon 10 of the HSD17B3 gene, in a subject with 17 beta-HSD 3 deficiency, is reported. Reconstitution experiments with recombinant protein reveal that substitution of tyrosine for cysteine at position 268 of 17 beta-HSD type 3 abrogates the enzymatic activity. This finding brings to 20 the number of mutations in the HSD17B3 gene that cause male undermasculinization.

17β-hydroxysteroid dehydrogenase 3 deficiency in a male pseudohermaphrodite

“…The majority of these mutations have been reconstituted by transient expression in cultured cells, and their functional consequences determined (7)(8)(9)(10)(11)(12)(13)(14)(15). All mutations so far identified appear to be inherited in an autosomal recessive pattern, requiring affected individuals to be homozygous or compound heterozygous for a mutation (17) ( Table 2).…”

“…To date, a total of 20 mutations of the HSD17B3 gene have been identified, including sixteen missense mutations, three splice junction abnormalities, and one small deletion that results in a frame shift mutation. Genetically, patients can be homozygous or compound heterozygous (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Molecular regulation of steroidogenesis in endocrine Leydig cells

“…The phenotype of affected individuals varies according to the severity of the mutation; this includes undescended testes, infertility, pseudohermaphroditism, and ambiguous genitalia. Mutations have been identified in the genes encoding the LH receptor (LHCGR) [22], INSL3 [23][24][25], and enzymes involved in testosterone biosynthesis [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Gene mutations affecting transcription factors associated with disruption of Leydig cell development and/or function in humans have also been described (see below).…”

Hydroxysteroid Dehydrogenases – Localization, Function and Regulation in the Testis

“…This autosomal recessive disorder manifests in males as undermasculinization characterized by hypoplasticto-normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts), but female external genitalia and the absence of a prostate (Boehmer et al, 1999;Lindqvist et al, 2001;Sinnecker et al, 1996;Ulloa-Aguirre et al, 1985).…”