Molecular Characterization of Two Known SRD5A2 Gene Variants in Mexican Patients With Disorder of Sexual Development.

Ortiz-López María Guadalupe,Sánchez-Pozos Katy,Menjivar Marta,Pirkko Vihko,Aguirre-Alvarado Charmina

doi:10.3389/fgene.2021.794476

Abstract

Background: The 5α-reductase type 2 deficiency (5α-RD2) is a specific form of disorder of sexual development (DSD). Pathogenic variants in the SRD5A2 gene, which encodes this enzyme, are responsible for 46,XY DSD. Objective: The objective of the study was to investigate the genetic etiology of 46,XY DSD in two Mexican families with affected children. Materials and methods: The SRD5A2 gene of the parents and affected children was screened in both families via polymerase chain reaction amplification and DNA direct sequencing. The role of genetic variants in enzymatic activity was tested by site-directed mutagenesis. Results: Subject 1 presented two variants: p.Glu197Asp and p.Pro212Arg. Subject 2 was homozygous for the variant p.Glu197Asp. The two variants were reported in early studies. The directed mutagenesis study showed that the p.Glu197Asp and p.Pro212Arg variants lead to a total loss of enzymatic activity and, consequently, abnormal genitalia development in the patients. Conclusion: These results suggest that p.Glu197Asp and p.Pro212Arg are pathogenic variants that lead to the phenotypic expression of DSD. 5α-RD2 is of extreme importance not only because of its frequency (it is rare) but also because of its significance in understanding the mechanism of androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior.

Highlights

Disorders of sex development (DSD) comprise a varied group of rare inherited conditions characterized by inconsistency among the anatomical, gonadal, and genetic sex (Lee et al, 2006)
In 1974, 5α-reductase type deficiency (5α-RD2) was first described clinically and biochemically in studies of Dominican Republic subjects and in two siblings from Dallas, TX, United States (ImperatoMcGinley et al, 1974; Walsh et al, 1974). 5α-RD2 is an autosomal recessive 46,XY DSD caused by genetic variants in the SRD5A2 gene, manifested by variable degrees of undervirilization (Fan et al, 2020)
We identified two pathogenic variants in the SRD5A2 gene in two patients with 46,XY from two Mexican families

Summary

Introduction

Disorders of sex development (DSD) comprise a varied group of rare inherited conditions characterized by inconsistency among the anatomical, gonadal, and genetic sex (Lee et al, 2006). The 5-alpha reductase type 2 deficiency (5α-RD2) is a rare cause of undefined genitalia in male children (Acién and Acién, 2020). The differential diagnosis of DSD due to 5α-RD2 is complex because other forms of DSD overlap with alternate male DSD, such as androgen insensitivity syndrome (partial form) and testosterone synthesis defects. 5α-RD2 is an autosomal recessive 46,XY DSD caused by genetic variants in the SRD5A2 gene, manifested by variable degrees of undervirilization (Fan et al, 2020). The 5α-RD2 manifests as failed or partial masculinization of external genitalia with normal Wolffian ducts, due to impaired activity of the 5-alpha reductase type 2 enzyme (3-oxo-5-alpha-steroid 4 dehydrogenase, 5α-R2). Pathogenic variants in the SRD5A2 gene, which encodes this enzyme, are responsible for 46,XY DSD

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Discussion

Conclusion