Autosomal dominant hypocalcemia types 1 and 2 (autosomal dominant hypocalcemia) - Genes CASR or GNA11.
Hypocalcemia is autosomal dominant disease characterized by low concentrations of calcium in the blood (hypocalcemia). Affected individuals may have an imbalance of other blood molecules and hyperphosphatemia or hypomagnesemia. Some people with autosomal dominant hypocalcemia also have hypoparathyroidism. Parathyroid hormone is involved in the regulation of calcium levels in the blood. Abnormal levels of calcium and other molecules in the body can cause a variety of signs and symptoms, although nearly half of those affected have no associated health problems.
Common characteristics include autosomal dominant hypocalcemia Carpopedal and muscle cramps, paresthesias and neuromuscular irritability in various parts of the body. In severe cases of the disease, individuals have seizures, usually in infancy or childhood. Sometimes these symptoms occur only during episodes of illness or fever. In addition, some people have hypercalciuria, which can lead to nephrocalcinosis or nephrolithiasis. These changes can damage the kidneys and impair its function. A small percentage of people seriously affected besides hypocalcemia, have characteristics of renal impairment called Bartter 's syndrome. These characteristics may include hypokalemia and hyperaldosteronism blood. This imbalance of molecules can enhance blood pH, causing metabolic alkalosis.
This disease is due to mutations in genes CASR and GNA11. When the disease is due to mutations in the CASR gene is called hypocalcemia autosomal dominant type 1. When the disease is due to mutations in the GNA11 gene is called hypocalcemia autosomal dominant type 2 proteins encoded from these genes act together to regulate the concentration of calcium in the blood.
CASR gene, located on the long arm of chromosome 3 (3q13), encodes a protein called calcium sensing receptor (CaSR). Calcium molecules bind to the CaSR protein, allowing the protein control and regulate the amount of calcium in the blood. The CaSR protein is abundant in cells of the parathyroid glands. When large amounts of calcium bind CaSR in the parathyroid glands, the parathyroid hormone coding is blocked, preventing the release of more calcium in the blood. Signaling CaSR also blocks the growth and proliferation of cells that compose the parathyroid glands. The CaSR protein is also found in kidney cells.
The GNA11 gene, located on the short arm of chromosome 19 (19p13.3), encodes a component, alpha (?) subunit of a complex protein called guanine nucleotide binding protein (G protein). Each protein G consists of three subunits called alpha, beta and gamma. Specifically, the protein encoded from GNA11 gene, termed G?11, is the alpha subunit for a G protein termed G11. This protein plays many roles in cells. Among others, it intervenes CaSR to act on the processes that regulate calcium levels in the blood. Is also involved in growth, proliferation and apoptosis of cells in tissues throughout the body, including the eyes, skin, heart and brain.
They have identified several mutations in the CASR gene and at least 5 GNA11 gene mutations in people with autosomal dominant hypocalcemia. These mutations change amino acids in CaSR and G?11. These changes (called activating mutations) cause excessive activity of the corresponding protein. CaSR altered protein is more sensitive to calcium, it can stimulate signaling G?11 even at low calcium concentrations. Similarly, the altered protein G?11 continues transmitting signals to avoid increases calcium, even when the concentrations in the blood are very low. As a result, the concentrations of calcium in the blood remain low, causing hypocalcemia. Calcium plays an important role in controlling muscle movements and deficiency of this molecule may lead to muscle cramps or spasms. Deterioration processes that increase calcium, can also alter the normal regulation of other molecules, such as phosphate and magnesium, leading to other autosomal dominant hypocalcemia signs. Studies show that the lower the concentration of calcium in the blood, the more severe symptoms of the disease.
This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to result in the alteration. In most cases, an affected person inherits the mutation from an affected parent. A small number of cases are due to new mutations in the gene and occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform detection of mutations associated with autosomal dominant hypocalcemia, by complete PCR amplification of the exons of the CASR and GNA11, respectively, genes and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).