MGA loss-of-function variants cause premature ovarian insufficiency
Shuyan Tang, … , Feng Zhang, Zi-Jiang Chen
Shuyan Tang, … , Feng Zhang, Zi-Jiang Chen
Published November 15, 2024
Citation Information: J Clin Invest. 2024;134(22):e183758. https://doi.org/10.1172/JCI183758.
View: Text | PDF
Research Article Genetics Reproductive biology

MGA loss-of-function variants cause premature ovarian insufficiency

Abstract

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/− female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.

Authors

Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen

×

Figure 5

Accelerated depletion of ovarian reserve in Mga+/− female mice.

Options: View larger image (or click on image) Download as PowerPoint
Accelerated depletion of ovarian reserve in Mga+/− female mice. (A) Repr...
(A) Representative images of reconstructed 3D ovaries. Mouse oocytes collected at P0 were stained with TRA98; oocytes collected at 4M and 8M were costained with DDX4 and P63 antibodies. Data analysis was conducted by spot transformation using Imaris software. Spots representing oocytes are colored based on size. Small oocytes with small diameter between 14 and 40 μm, which represent quiescent oocytes in primordial follicles, are indicated as gray spots. Large oocytes with diameter greater than 40 μm, representing growing oocytes in secondary and antral follicles, are indicated as red spots. The scale bars indicate 100 µm at P0 and 300 µm at both the 4M and 8M time points. The enlarged views are magnified to 5 times the original scale. (B) The number of total oocytes per ovary at P0, 4M, and 8M, respectively. Significantly fewer total oocytes were observable in Mga+/− females compared with WT females at 8M. (C) Statistical summary of small and large oocytes per ovary in 4M and 8M between Mga+/− and WT females. Data in B and C show means ± SEM for at least n = 6 mice per genotype for each time point and can be found in the Supporting Data Values file. (D) H&E staining of ovarian sections of 8M mice. (E) Box plot showing statistical summary of primordial, primary, secondary, and antral follicles per ovary in WT (n = 9) and Mga+/− (n = 8) mice age 8M. Central line of box plots denotes median; box marks interquartile range and whiskers 1.5× interquartile range. Statistical significances of B, C, and E were determined using a 2-sided unpaired t test. *P < 0.05; **P < 0.01.