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Finding the Genetic Cause of a Form of Hyperparathyroidism

Researchers have identified genetic differences that can cause familial isolated hyperparathyroidism (FIHP), a discovery that could lead to improved testing for the disorder and may one day lead to improved treatment for people with either too much or too little parathyroid hormone (PTH). PTH stimulates release of calcium from bones when blood calcium levels are too low. FIHP is an inherited disease, and is one of several conditions characterized by high basal levels of PTH that lead to dangerous elevations of blood calcium levels. This calcium dysregulation in FIHP results in symptoms that may include kidney stones, osteoporosis, and neuromuscular problems like weakness, drowsiness, and depression. Other causes of excess PTH that may yield similar symptoms include various distinct syndromes, and most commonly benign or malignant tumors of the parathyroid gland—conditions that may be best treated in different ways. Understanding the genetics of FIHP would potentially allow it to be differentiated more easily and accurately from other causes of excess PTH, allowing clinicians to tailor treatment to patient needs. Toward this goal, researchers studied families that have FIHP to pinpoint specific genetic differences unique to people with this disease.

Focusing initially on a subset of gene regions in DNA from eight unrelated families in which some family members have FIHP, the scientists looked for rare genetic variations that were present in people with FIHP, but not in their family members without the disease. This approach helped them narrow the investigation to 30 genes of interest, which they examined in detail in 32 other families where two or more individuals had symptoms of FIHP. In this way, they discovered that FIHP-affected members of several of the families had one or more rare mutations in the gene GCM2. This gene encodes a protein known to be involved in development and function of the parathyroid gland by turning on other genes needed for parathyroid function. Interestingly, other GCM2 variations had previously been shown to reduce expression of those genes, leaving people without enough PTH; and mice genetically engineered to lack GCM2 do not develop functional parathyroid glands. Thus, it was surprising that some GCM2 variations have the opposite effect, leading to too much PTH in people with FIHP. The research team showed that at least some of the GCM2 mutations found in families with FIHP increased the activation of other genes by the GCM2-encoded protein, resulting in excess PTH. Through additional experiments, they showed that some of the FIHP-associated GCM2 mutations alter an important regulatory region that is needed to prevent over-activation of the other parathyroid genes.

Importantly, people with FIHP in most of the families that participated in the study were found not to have mutations in GCM2, suggesting that other genetic causes of FIHP remain to be discovered. But the discoveries that GCM2-activating mutations can cause excess PTH, while inactivating mutations can result in insufficient PTH, suggest this gene or the protein it encodes could be valuable drug targets for treating some people whose PTH levels are either too high or too low.