对一个台湾家族的遗传分析确定了 DMRT3-OAS3 的相互作用，该相互作用通过调节 ESR1 的表达而参与人类性别分化。

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

机构信息

Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

出版信息

Fertil Steril. 2020 Jul;114(1):133-143. doi: 10.1016/j.fertnstert.2020.03.008. Epub 2020 Jun 16.

DOI:10.1016/j.fertnstert.2020.03.008

PMID:32553473

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 2',5'-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 DMRT3-OAS3 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.

摘要

目的

鉴定一个台湾 46,XY 性反转和尿道下裂的常染色体显性遗传家族中复发性性别发育障碍（DSD）的遗传病因。

设计

遗传和功能研究。

地点

学术医院。

患者

一个由 22 名成员组成的三代家族，其中 8 例为 46,XY DSD，其中 4 例为 46,XY 男性到女性性反转，4 例为 46,XY 男性尿道下裂。

干预

无。

主要观察指标

外显子组测序和体外蛋白及 RNA 分析结果。

结果

所有 DSD 患者均携带 doublesex 和 mab-3 相关转录因子 3（DMRT3；rs187176004，c.A815C，p.K272T）和 2',5'-寡腺苷酸合成酶 3（OAS3；rs16942374，c.G2606A，p.R869H）基因的杂合错义突变。DMRT3 突变增加了雌激素受体 1（ESR1）的表达。野生型 DMRT3 与 OAS3-RNase L 复合物结合后，促进 ESR1 mRNA 的降解。然而，DMRT3-OAS3 复合物与 ESR1 mRNA 和 RNase L 的相互作用较弱，最终阻止了 ESR1 mRNA 的降解。在患者的睾丸中证实了 DMRT3、OAS3 和 RNase L 之间的相互作用。