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Familial Hypocalciuric Hypercalcaemia type 1 (FHH1)

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p678

2026-06-22

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FHH1 (OMIM #145980) is caused by heterozygous loss- of- function mutations in the CASR gene on chromosome 3q21 as described here. FHH1 is transmitted as an autosomal dominant disorder and is highly penetrant. FHH1 is the most common cause of the FHH phenotype accounting for approximately 65% of FHH cases in the database from McGill University summarizing many known CASR mutations (CaSRdb: calcium- sensing receptor database: https:// www.casrdb.mcgill.ca).

More than 130 different mutations of the CASR have been re ported in patients with FHH1. Most commonly (>85% of cases), a missense mutation reduces the function of the CaSR. Twenty- eight codons, equivalent to more than 20% of all mutated codons, are found to be mutational hot spots for missense mutations. They are clustered in three regions: the second loop of the ECD, the VFT cleft region with calcium binding sites, and the region encompassing TMD 6 and 7.

The CaSR and its mutant forms have been functionally characterized in vitro in overexpression systems in which a mammalian expression vector with a cDNA insert is transfected into HEK293 (human embryonic kidney 293) or COS (CV- 1 in Origin with SV40 gene) cells either transiently or stably. The cDNA encodes either a wild- type or mutant CaSR. More physiological renal or parathyroid cell model systems do not exist in which to study the function of the CaSR and its mutant forms. Altered CaSR signalling in renal tubular or parathyroid chief cells in vivo leads to altered CaSR signalling and excessive PTH secretion in the presence of hypercalcaemia and to increased renal calcium reabsorption and hypocalciuria, respectively. Mutated residues within the VFT cleft region likely affect binding of calcium or alter the conformational changes of the CaSR upon calcium binding. Specific VFT residues may act as an intramolecular switch to allow access to and binding of calcium within the VFT cleft region. When mutated, this can lead to opposing effects on CaSR signalling. Approximately 50% of mutations in CASR in FHH1 result in reduced cell surface CaSR levels due to impaired synthesis and/ or increased degradation of the CaSR. Mutant CaSRs can be trapped intracellularly being unable to exit the endoplasmic reticulum (ER) or Golgi apparatus, or there may be defective trafficking of the receptor from the ER to the plasma membrane. Some mutant CaSRs are unable to couple to G proteins to activate intracellular cell signalling path ways. In addition, there may be dominant- negative effects of the mutant CaSR to reduce the function of the wild- type CaSR through the dimerization. As noted just here, mature cell surface CaSRs are thought to assemble as dimers. However, coexpressed wild- type CaSRs might also increase transport of mutant CaSR receptors to the plasma membrane via ADIS. Rarely, a nonsense, deletion, insertion, or splice- site mutation will lead to a truncated, in active CaSR, but this occurs it seems in less than 15% of cases.