MGA is a transcriptional repressor or activator depending upon the presence of its binding partner, MAX (154950) (Hurlin et al., 1999).

By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) obtained a partial MGA clone, which they designated KIAA0518. RT-PCR analysis detected variable MGA expression in all human tissues examined, with highest expression in ovary, followed by testis, placenta, and kidney. Lowest expression was detected in pancreas and spleen.

Hurlin et al. (1999) cloned mouse Mga. The deduced 3,006-amino acid protein has an N-terminal T-box domain and a C-terminal basic helix-loop-helix leucine-zipper domain. The T-box domain is predicted to interact with specific DNA sequences that are bound by T brachyury (T; 601397), and the basic helix-loop-helix domain is predicted to bind E-box sequences. Northern blot analysis of rat PC12 cells detected Mga at approximately 14 kb. In situ hybridization of embryonic mouse showed highest Mga expression in limb buds, branchial arches, and tail region.

Uranishi et al. (2021) noted that MGA contains a basic helix-loop-helix leucine zipper (bHLHZ) domain and a DNA-binding domain called the T-box domain.

By radiation hybrid analysis, Nagase et al. (1998) mapped the MGA gene to chromosome 15.

Using FISH, Hurlin et al. (1999) mapped the MGA gene to chromosome 15q15. They mapped the mouse Mga gene to a central region of chromosome 2 that shares homology of synteny with human chromosome 15q15.

Using a yeast 2-hybrid assay, Hurlin et al. (1999) found that the mouse transcription factor Max interacted with Mga. Coimmunoprecipitation analysis confirmed that Max and Mga interacted in transfected HEK293 cells. EMSA revealed that Mga required Max for binding to the E-box sequence CACGTG. The isolated T-box of Mga bound the brachyury T-box-binding site in the absence of Max. Mga repressed transcription of a reporter driven from a T-box-binding site, but coexpression of Mga with Max caused transcriptional activation from the T-box-binding site. Expression of Mga with Max, but not Mga alone, activated transcription from a reporter containing the E-box site.

Using mouse embryonic stem cells (ESCs) lacking either the bHLHZ or T-box domain, Uranishi et al. (2021) demonstrated that both domains repressed distinct sets of genes, with substantial numbers of meiosis-related genes included in both gene sets. In addition, bHLHZ was crucially involved in repressing the expression of meiosin, which plays essential roles in meiotic entry with Stra8 (609987), revealing at least some of the molecular mechanisms that link negative and positive regulation of meiotic onset.

Using exomewide gene-based case-control analysis in a cohort of 1,027 Chinese women with premature ovarian failure (POF) and 2,733 ethnically matched control women, Tang et al. (2024) discovered significant enrichment for presumed loss-of-function variants in the MGA gene, which were present in heterozygosity in 27 patients (2.6% of cases) but in none of the controls. Exome screening in 4 additional POF cohorts, 2 Chinese and 2 from the US, resulted in identification of an overall total of 37 distinct presumed loss-of-function mutations in the MGA gene present in heterozygosity in 38 patients, accounting for approximately 2.0% of the total 1,910 POF cases analyzed. Only 5 of the variants were found in the gnomAD or BRAVO databases, at exceedingly rare frequencies, and all variants were predicted to induce nonsense-mediated decay. Family members were available for study in 10 of the 38 families; in those families, the mutation was maternally inherited from an affected mother in 2 cases (see 616061.0001 and 616061.0002), was paternally inherited in 4 cases, and arose de novo in 4 cases (see 616061.0003).

Tang et al. (2024) induced a frameshift mutation in exon 3 of the Mga gene in C57BL/6 mice and observed that homozygosity for the mutation was embryonic lethal. Breeding assays showed that female heterozygotes had a lower cumulative number of pups compared to their wildtype littermates and ceased giving birth more than 4 months earlier than wildtype females. Male heterozygotes showed no obvious abnormalities in sperm characteristics or fertility compared to wildtype males. The authors used fluorescence immunostaining of oocyte markers and 3D ovarian images to assess ovarian reserve and observed that the number of total oocytes, small quiescent oocytes in primordial follicles, and large growing oocytes in secondary and antral follicles all showed a significant decrease at 8 months of age in the mutant females compared to wildtype mice. Histologic examination of ovarian sections confirmed the reduction in primordial and growing follicles in the mutant female mice compared to wildtype female littermates. These findings suggested that follicle depletion is accelerated in Mga +/- females and that Mga plays a role in maintaining ovarian reserve.

Washkowitz et al. (2015) generated conditional knockin mice carrying a loss-of-function mutation in the Mga gene, resulting in a truncated fusion protein that carried a beta-geo reporter under the control of the Mga promoter. Heterozygous mice were born at the expected mendelian frequency and were viable and fertile, whereas the homozygous mouse embryos developed to the blastocyst stage but died during the process of implantation. Mga was expressed in the pluripotent inner cell mass (ICM) and inner pluripotent epiblast (EPI) of the periimplantation embryo, and the ICMs of the blastocysts isolated from the homozygous embryos and blastocysts with Mga knockdown failed to thrive in vitro. Similarly, embryonic stem cells (ESCs) homozygous for conditional Mga mutation displayed a growth defect in vitro. Furthermore, embryos homozygous for the Mga mutation had increased apoptosis, indicating that cell death was the cause of the embryonic lethality in homozygous mice. Early differentiation of the ICM was not affected by the absence of functional Mga, but embryos lacking Mga lost pluripotent cells during diapause. Expression of Odc1 (165640), the rate-limiting enzyme in the conversion of ornithine into putrescine in the synthesis of polyamines, was reduced in Mga mutant cells, and the survival of mutant ICM cells as well as ESCs was rescued in culture by the addition of exogenous putrescine.

Mouse germ cells produce a variant of Mga during meiosis by alternative splicing, in which a specific portion of the eighteenth intron of the Mga locus, designated Mga exon19a, is used as the variant-specific exon. The splice variant lacks the C-terminal portion, including the bHLH domain. Kitamura et al. (2022) generated mutant mice lacking the alternative splice variant of Mga by deleting the Mga exon19a sequence in the genome. Mice both heterozygous and homozygous for the exon19a deletion were viable and fertile. Moreover, loss of the Mga splice variant did not result in any apparent abnormalities in spermatogenesis and did not affect the spermatogenic cycle, even though Mga knockdown analysis in immortalized spermatogenic cell lines confirmed that Mga was indeed involved in the repression of meiosis-related genes.