The mutation in the KCTD1 gene leads to kidney defects that can eventually lead to metabolic bone disease
Boston – While investigating the underlying causes of a rare skin disorder, a researcher at Massachusetts General Hospital (MGH) discovered a previously unknown mechanism in the kidneys that is important for regulating levels of magnesium and calcium in the blood.
The discovery described in the journal Cell Reports, Highlights the role of a previously unknown gene called KCTD1 that directs the production of a protein that regulates the kidneys’ ability to reabsorb magnesium and calcium from the urine and return it to the bloodstream.
The gene mutation that causes KCTD1 loss leads to defects in the nephron, the basic filtering units of the kidney, according to the report of Alexander G. Marnerus, MD, Ph.D., researcher at MGH’s Skin Biology Research Center and Associate Professor of Dermatology at Harvard Medical School. KCTD1 is particularly important in nephron sectors involved in regulating the reabsorption of salt, magnesium, and calcium from filtered urine into the bloodstream.
Nephron defects resulting from the loss of KCTD1 in turn lead to abnormally low levels of magnesium (hypomagnesemia) and calcium (hypocalcemia) in the bloodstream. An abnormal drop in blood calcium levels causes the parathyroid hormone-producing glands in the neck to become overactive, a condition known as secondary hyperparathyroidism. The resulting high levels of parathyroid hormone release calcium from the bones in an effort to counteract the low levels of calcium in the blood, which ultimately leads to a loss of bone mass.
Marneros described the initial identification of kidney abnormalities that occur as a result of KCTD1 deficiency in a study published in 2020 in the journal Developmental Cell, which showed that KCTD1 deficiency in mutated mice leads to progressive kidney abnormalities, which partially resemble the results in patients. With chronic kidney disease. In fact, he noted that patients with KCTD1 mutations also developed chronic kidney disease with renal fibrosis (scarring of kidney tissue). These results indicate that KCTD1 plays an important function in the kidneys.
In the current study, Marneros reported that KCTD1 acts in a part of the nephron known as the distal nephron to regulate the reabsorption of electrolytes from the urine into the bloodstream and maintain balanced (homeostasis) levels of these electrolytes.
“The distal nephron is important not only for salt reabsorption, but also for magnesium and calcium re-absorption, and this study shows that KCTD1 is important for the distant nephron’s ability to reabsorb these electrolytes from the urine,” he says.
The paper provides a detailed description of changes in proteins that transport electrolytes across membranes in the distal nephron when KCTD1 is missing. Collectively, the results revealed that KCTD1 is the main regulator of the distal nephron’s ability to not only reabsorb salt but also magnesium and calcium from the urine, thus maintaining a healthy balance.
The study was supported in part with funding from MGH and the National Institutes of Health.
About Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the largest teaching hospital at Harvard Medical School. The Mass General Research Institute conducts the nation’s largest hospital-based research program, with annual searches of more than $ 1 billion and engaging over 9,500 researchers working in more than 30 institutes, centers and departments. In August 2020, Mass General was ranked sixth on US News & World Report’s list of America’s “Best Hospitals”.
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