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Three Cystic Kidney Disease Genes Related to Hyperemesis Gravidarum (HG)

A possible genetic pathway related to hyperemesis gravidarum (HG), a severe form of morning sickness that affects Kate Middleton, wife of Prince William and mother of young Prince George (see photo), and 0.3 to 2% of all pregnancies, has been identified by Marlena Fejzo, Ph.D., an assistant researcher of hematology–oncology at the David Geffen School of Medicine at UCLA and an assistant professor of maternal and fetal medicine at the Keck School of Medicine of USC, and a team of colleagues. HG disease leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. Sixty years ago, HG was the cause of death in 10% of pregnancies, and, even today, it accounts for over 225,000 hospital discharges in the U.S. each year and 15% of HG-afflicted women in the U.S. choose therapeutic termination of pregnancy. The disease remains associated with significant maternal morbidity, including Wernicke’s encephalopathy, renal failure, kidney failure, liver function abnormalities, esophageal rupture, and post-traumatic stress. Genetics has long been thought to play a role in HG, but no definitive study had previously been done. Using exome sequencing in five HG pedigrees and over 470 controls, the Fejzo team identified three kidney disease genes [PKD1, polycystic kidney disease 1 (associated with 85% of autosomal dominant polycystic kidney disease in humans)], PKHD1 (polycystic kidney and hepatic disease 1, associated with autosomal recessive polycystic kidney and hepatic disease 1 in humans), and LAMA5 (laminin alpha 5, a hypomorphic mutation in this gene has been shown to cause polycystic kidney disease in mice) that were found to be variant in the HG families, but in none of the controls. These three genes are normally involved in renal tubular proliferation, differentiation, and development. The researchers presented their work in poster form at the ASHG 2014 annual meeting in San Diego, California, in mid-October. They believe that their results relate HG to kidney malfunction and that mutations in these three kidney genes may account for a substantial amount of the risk associated with HG. The finding that kidney genes are related to HG provides new avenues for diagnosis, research, and therapy, the researchers say.