SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation

Abstract

One hundred and forty-six index patients with 46,XY DSD in whom gonads were confirmed as testes were consecutively studied for a molecular diagnosis during the period 2002-2010. AR gene was analysed in all patients as the first candidate gene, yielding a mutation in 42.5% of cases and SRD5A2 gene was analysed as the second candidate gene, resulting in the characterization of 10 different mutations (p.Y91D, p.G115D, p.Q126R, p.R171S, p.Y188CfsX9, p.N193S, p.A207D, p.F219SfsX60, p.R227Q and p.R246W) in nine index patients (6.2% of the total number of 46,XY DSD patients). One of the mutations (p.Y188CfsX9) has never been reported. In addition, we genotyped SRD5A2 gene p.V89L and c.281+15T>C polymorphisms in 46,XY DSD and in 156 normal adult males and found that patients with SRD5A2 mutations or without a known molecular diagnosis presented a higher frequency of homozygous p.L89, homozygous TT and combined CCTT genotypes compared with controls. This result suggests that 46,XY DSD patient phenotypes may be influenced by SRD5A2 polymorphism genotypes. SRD5A2 gene mutations may not be as infrequent as previously considered in 46,XY DSD patients with variable degrees of external genitalia virilization at birth and normal T production and appears to be the second aetiology in our series.

AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity

“…In our series, all patients with SRD5A2 mutations presented the homozygous genotype V89/CC for two polymorphisms (rs523349: p.V89L and rs522638: c.281 + 15T>C) which has not been associated with hypospadias (Fernandez-Cancio et al, 2011), and, therefore, it cannot be involved in the phenotype.…”

“…SRD5A2 gene analysis was performed as indicated by Fernandez-Cancio et al (2011) in the same laboratory.…”

“…Although the serum T/DHT ratio is an important screening tool for identifying patients with possible 5a-reductase deficiency, cut-off values for diagnosis remain uncertain. Cases with a molecular diagnosis of 5a reductase type 2 deficiency and T/DHT ratio below the suggested cut-off values have been reported (Fernandez-Cancio et al, 2011).…”

A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency

“…In in vitro studies, the POR p.A503V variant decreased P450c17 catalytic activity in 60% of the population [25] but did not change P450c21 activity [26]. The SRD5A2 p.V89L allele reduced the conversion of testosterone into dihydrotestosterone in 30% of cases and was more frequent in males with disorders of sex development in comparison to controls [27]. Conversely, some variants are associated with increased androgen synthesis, with the HSD17B5 c.-71A>G allele increasing protein expression and determining a 20% increase in serum testosterone levels and an increased risk for polycystic ovary syndrome [19].…”

Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development

“…A study from our Dutch colleagues reported that 13/18 cases previously thought to have AIS were ultimately found to have mutations in HSD17B3 (9). Amalgamated data from the Dutch nationwide survey (1) and three Spanish reports (10,18,19) are shown in Fig. 2B, estimating diagnostic proportions among paediatric cohorts.…”