User:Carterjmatte/STAG3

Lead
Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.

Role In Meiosis

STAG3 associates with several key structures through out meiosis. As shown in spermatocytes, STAG3 interacts with the synaptonemal complex or SC, which facilitates the alignment of sister chromosomes. Furthermore, STAG3 associates with axial elements during prophase, which are responsible for packaging the sister chromosomes via loops. Once the axial elements interact with the SC they are termed as lateral elements. STAG3's involvement with these three complexes suggest its profound role in the cohesion of sister chromatids. Moreover, STAG3 has also been detected in the centromeres and telomeres of sister chromosomes, implying a potential role in telomere cohesion as well.

The role of STAG3 changes once prophase elapses. This is supported by the change in localization of STAG3 between metaphase and anaphase. STAG3 disassociates with the axes, but stays localized in the centromere, during the transition. Once anaphase in achieved, STAG3 is not observed anywhere in the chromosome architecture, further emphasizing its primary function in chromosome alignment and packaging.

Variants

Deficiencies in STAG3 production can result in severe complications during meiosis. In the aging and age-related disease strain of mice, SAM, many cohesin proteins, including STAG3, are shown in reduced number. This supports the widely believed role of cohesin deficiency in aneuploidy as a result of aging.

Infertility is a widely studied outcome of STAG3 deficiency or knockout. In a study, a homozygous knockout of STAG3 gene was made in a strain of mice. The males that had the double knockout had their testis reduced to half the size of the wild type mouse. Female mice also experienced infertility. This outcome is largely believed to be due to the absence of STAG3. While all other cohesin subunits were able to assemble, the loss of STAG3 impaired the synapsis of sister chromosomes, as shortened or no axial elements and SCs were able to be formed, causing the spermatocytes and oocytes to forgo meiosis upon reaching prophase.

A homozygous 1-bp deletion inducing a frameshift mutation in STAG3 causes premature ovarian failure. Loss of function mutations in STAG3 can result in stifling of ovary development in utero. Much like the infertile STAG3 knockout male mice models, female mice also experienced meiotic arrest during prophase. Since females are born with a finite amount of oocytes, a significant deficiency in STAG3 can result in a depletion of viable eggs early in life.

In males, variants can result in azoospermia, or not motile sperm. To elaborate, a missense mutation, which resulted in a premature stop codon, leading to a complete loss of function in STAG3 caused infertility in men. Another mutation that has been identified changes a neutral amino acid residue, leucine, to a positively charged amino acid, arginine. This causes debilitating protein misfolding, preventing the protein from taking on the correct conformation, rendering it useless. It has been identified that variants in the STAG3 gene can be inherited in an autosomal recessive manner.