A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

Abstract

Objective: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5α-reductase type 2 deficiency. Patients and Methods: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5α-reductase type 2 were assessed. Results: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. Conclusion: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5α-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients.

Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias

“…Functional research exists already regarding the p.R227Q, p.G203S and p.R246Q mutation sites (10)(11)(12). To assess the functional effects of p.L20P and p.R62S, we performed in silico predictions.…”

Phenotypic and molecular characteristics in eleven Chinese patients with 5α‐reductase Type 2 deficiency

“…The p.G203S mutation, the most frequent mutation found in this study, has been repeatedly reported in patients from East Asia, including China, Korea and Thailand, as well as Mexico . In vitro functional assay revealed that the enzymatic activity was retained in approximately 40% of the cases . Therefore, patients heterozygous for this mutation have been reported to have a more masculine phenotype in previous investigations .…”

“…The R227Q mutation, identified in patient 2, has been reported to significantly reduce 5α‐reductase activity to 3·2% in vitro and has only been reported in Asian patients from China, Vietnam, Japan, Mongolia and Laos . The p.Q6X mutation detected in patient 11 was first identified in a Japanese individual and has only been reported in patients from East Asian countries . The p.N193S mutation, carried by patient 5, has been reported in patients of Spanish, African and Chinese origin .…”

“…The nucleotide variation p.V89L and the frameshift mutation c.655delT were identified in patient 1, who presented with a nearly complete male phenotype and a micropenis. It was demonstrated that the c.655delT mutation caused a translational frameshift at codon 219 of the SRD5A2 gene, leading to a nearly complete loss of enzymatic activity . The variant p.V89L is considered to be one of the susceptibility factors for hypospadias and may lead to impairment in normal virilization of the external genitalia, although no discernible effect on the development of micropenis has reportedly been observed .…”

Genetic sequencing of a patient with Kallmann syndrome plus 5α-reductase type 2 deficiency

“…The elevated T/DHT ratio post-HCG stimulation is more sensitive and reliable in diagnosis of 5a-RD3 and helpful to distinguish between androgen insensitive syndrome and other conditions arising from T synthesis defects. The diagnostic cut-off point of T/DHT ratio has not been precisely defined, varied from 3.6 to 18 in diverse ethnic groups pre or after HCG stimulation 456. Obviously, high T/DHT ratio of 26.4 after HCG stimulation is another reason for the diagnosis of mild 5a-RD.…”