Volume 114, Issue 1, Pages 133–143
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.
To identify the genetic etiology of recurrent disorders of sex development (DSDs) in a Taiwanese family with 46,XY sex reversal and hypospadias.
Genetic and functional studies.
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.
Main Outcome Measure(s)
Results of exome sequencing and in vitro protein and RNA analyses.
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.
Our results indicate that DMRT3 and OAS3 are involved in human DSDs by controlling ESR1 expression.