Chronic Mountain Sickness, Susceptibility To

Description

Chronic mountain sickness (CMS), or Monge disease, represents a state of maladaptation to high-altitude hypoxia in a member of a population acclimatized to high altitudes. CMS is characterized by severe polycythemia and an array of neurologic symptoms, including headache, fatigue, somnolence, and depression. Often, people with CMS suffer from strokes and myocardial infarctions in early adulthood because of increased blood viscosity. Studies have shown that CMS is common in Andeans, found occasionally in Tibetans, and absent from the Ethiopian population living on the East African high-altitude plateau (summary by Zhou et al., 2013). Acute mountain sickness (see pulmonary edema of mountaineers, 178400) is experienced by unacclimatized travelers exposed to high altitude.

Molecular Genetics

Zhou et al. (2013) sequenced and compared whole genomes of 20 Andean subjects (10 with CMS and 10 without). The authors identified 11 regions genomewide with significant differences in haplotype frequencies, consistent with selective sweeps. In these regions, 2 genes on 12q13, an erythropoiesis regulator (SENP1; 612157) and an oncogene (ANP32D; 606878), had a higher transcriptional response to hypoxia in individuals with CMS relative to those without, as measured in fibroblasts exposed to hypoxic conditions for 24 hours. Zhou et al. (2013) further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Zhou et al. (2013) concluded that their study provided an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identified potentially targetable mechanisms for CMS treatment.

Pathogenesis

Azad et al. (2016) reprogrammed fibroblasts from CMS and non-CMS individuals living at high altitude in Peru, as well as sea level-dwelling Peruvian controls, and generated induced pluripotent stem cells that were then transformed into erythroid cells. Following exposure of the cells at the embryoid body stage to 5% O2 for 28 days, sea-level controls had a modest (5-fold) increase in expression of the erythroid marker CD235A (GYPA; 617922) and non-CMS individuals had no change in CD235A expression, whereas CMS subjects had a marked (over 50-fold) change in CD235A expression, suggesting a genetically controlled polycythemic response to hypoxia. Knockdown of SENP1 resulted in a marked reduction in CD235A expression in the response of CMS cells to hypoxia. Overexpressing SENP1 in non-CMS cells resulted in a polycythemic phenotype. Expression of BCLXL (BCL2L1; 600039) and, particularly, GATA1 (305371) increased significantly in CMS cells undergoing hypoxia. Sumoylation of GATA1 in CMS cells was much lower than in non-CMS cells. Azad et al. (2016) concluded that GATA1 activation mediated by SENP1 desumoylation is essential for the polycythemic response in CMS. Furthermore, they concluded that the differential expression and responses of GATA1, an essential downstream target of SENP1, and BCLXL are key mechanisms underlying CMS pathology.