Genetic analysis of a Taiwanese family identifies a DMRT3-OAS3 interaction that is involved in human sexual differentiation through the regulation of ESR1 expression

We identified DMRT3 and OAS3 mutations in a Taiwanese family with recurrent disorders of sex development. DMRT3A815C induced ESR1 expression whereas the mutant DMRT3-OAS3 complex interacted less with RNase L, preventing ESR1 mRNA degradation.

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Volume 114, Issue 1, Pages 133–143

Authors:

Chia-Lung Tsai, Ph.D., Chi-Neu Tsai, Ph.D., Yun-Shien Lee, Ph.D., Hsin-Shih Wang, M.D., Ph.D., Li-Yu Lee, M.D., Chiao-Yun Lin, Ph.D., Shu Yuan Yang, Ph.D., Angel Chao, M.D., Ph.D.

Abstract:

Objective

To identify the genetic etiology of recurrent disorders of sex development (DSDs) in a Taiwanese family with 46,XY sex reversal and hypospadias.

Design

Genetic and functional studies.

Setting

Academic hospital.

Patient(s)

A three-generation family consisting of 22 members, with eight cases of 46,XY DSD, of whom four have 46,XY male-to-female sex reversal and four are 46,XY males with hypospadias.

Intervention(s)

None.

Main Outcome Measure(s)

Results of exome sequencing and in vitro protein and RNA analyses.

Result(s)

All patients with DSDs were found to carry heterozygous missense mutations in the doublesex and mab-3-related transcription factor 3 (DMRT3; rs187176004, c.A815C, p.K272T) and 2ʹ,5ʹ-oligoadenylate synthetase 3 (OAS3; rs16942374, c.G2606A, p.R869H) genes. The DMRT3 mutation increased estrogen receptor 1 (ESR1) expression. Upon binding with the OAS3-RNase L complex, wild-type DMRT3 promoted degradation of ESR1 mRNA. However, the DMRT3A815C-OAS3G2606A complex interacted less strongly with ESR1 mRNA and RNase L, ultimately preventing ESR1 mRNA degradation. The interactions between DMRT3, OAS3, and RNase L were confirmed in the patients’ testis.

Conclusion(s)

Our results indicate that DMRT3 and OAS3 are involved in human DSDs by controlling ESR1 expression.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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