DNA repair processes
The finding that WRN protein interacts with DNA-PKcs and the Ku protein complex, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ). WRN protein also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex). X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.WRN protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.WRN protein participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair.Evidence was presented that WRN protein plays a direct role in the repair of methylation induced DNA damage. This process likely involves the helicase and exonuclease activities of WRN protein that operate together with DNA polymerase beta in long patch base excision repair. Effects on cell structure and function
Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions. There are 35 different known mutations of WRN, which correspond to stop codons, insertions, or deletions that result in a frameshift mutation. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the WRNp protein.
A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea. Causes
The cause of POI is idiopathic in 90% of cases. Some cases of POI are attributed to autoimmune disorders such as autoimmune oophoritis, Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia, genetic disorders such as Turner syndrome and Fragile X syndrome, metabolic defects, and enzyme defects. One study showed a strong correlation between incidence of POI and certain variants in the inhibin alpha gene. Chemotherapy and radiation treatments for cancer can sometimes cause POI. The effect of chemotherapy or radiation is variable and in a mouse model, with results consistent with observations in humans, cyclophosphamide can result in an 87% reduction in primordial follicles 72 hours after administration. Women who have had a hysterectomy tend to go through menopause early and have a nearly twofold increased risk of POI. Almost any pelvic surgery has the potential to damage the ovary by affecting its blood supply or causing inflammation in the area resulting in POI. Galactosemia
Women who have inherited classic galactosemia (galactose intolerance) may develop primary ovarian insufficiency. Mechanism
The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles.