MGA loss-of-function variants cause premature ovarian insufficiency
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
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
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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

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Figure 4

Subfertility of Mga+/− female mice.

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Subfertility of Mga+/− female mice. (A) Schematic illustration of the ta...
(A) Schematic illustration of the targeting strategy used to generate Mga-mutated mice using CRISPR/Cas9 technology. (B) The sgRNA was designed to target exon 3 of mouse Mga, and the protospacer adjacent motif is indicated by the blue highlight. Sanger sequencing results of the WT and heterozygous Mga mutants showed 1 bp deletion plus 3 bp insertion (c.1344delinsGTA) was introduced in mouse Mga, resulting in a frameshift mutation (p.Ser448Argfs*13) of MGA. The mutated nucleotides and amino acids are highlighted in red. The termination codon is indicated by an asterisk. (C) Cumulative number of pups produced per female mouse through continuous breeding. Both WT (n = 8) females and Mga+/− (n = 8) females were mated with WT male mice. Asterisks indicate statistically significant differences between the 2 groups. (D) Statistical summary of breeding/reproductive features of Mga+/− and WT female mice, including maternal age at first litter, maternal age at last litter, average number of pups per litter, and average number of litters. Central line of boxplots denotes median, box marks interquartile range and whiskers ×1.5 interquartile range. Statistical significances of C and D were determined using a 2-sided unpaired t test. **P < 0.01; ***P <0.001.