Relative to the remarkable progress made in identifying the genetic basis of circadian rhythms and some specific sleep disorders, efforts to identify genetic variants associated with normal variation in sleep have progressed more slowly.
Hence, we tested the newly identified genetic variants associated with normal variation in menopausal age, in a population of approximately 2000 women from the Breakthrough Generations Study BGSS) who had EM, defined as menopause before the age of 46 years, plus 2000 matched controls.
Our data suggest that variants associated with normal menopausal age are also significant risk factors for EM.
Western blots showed reduced p53 protein expression in the majority of samples harboring SDHx variants compared with normal controls (Fig. 3A and B, upper panels).
We previously found that cellular ROS is significantly increased in CS/CSL patient samples harboring germline SDHx variants compared with normal controls (16).
ROS marker microscopy revealed significantly increased intracellular ROS levels in representative samples harboring SDHx variants compared with normal controls (Fig. 1B), with or without PTEN mutation, consistent with our previous finding (14).
Prior to the recent identification of 13 new variants associated with normal age at menopause, there were four loci reported, which were replicated in the more recent study, (13, 14, 15).
Thus, the aberrant splice variant interferes with normal KAP functioning and, as a consequence, increases the Cdk2-dependent proliferation of GBM cells (Fig. 2).
