Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism are genetic disorders affecting calcium homeostasis.
• The calcium-sensing receptor (CaSR) plays a critical role in regulating parathyroid hormone secretion and calcium levels.
• Mutations in the CaSR gene are known causes of these conditions.

Purpose of the Study:

• To identify and characterize novel mutations in the CaSR gene associated with FHH and neonatal severe hyperparathyroidism.
• To investigate the location and predicted functional impact of these mutations within the CaSR protein.

Main Methods:

• Direct sequencing of the CaSR gene to identify mutations.
• Analysis of mutation locations within the CaSR protein domains (extracellular, transmembrane).
• Review of previous genetic analyses in FHH families.

Main Results:

• Five novel missense mutations in the CaSR gene were identified: 228Arg-->Gln, 139Thr-->Met, 144Gly-->Glu, 63Arg-->Met, and 67Arg-->Cys.
• These mutations result in nonconservative amino acid substitutions, predicted to be in the extracellular domain of the CaSR.
• In some FHH families, mutations were not found in the protein-coding sequences, suggesting involvement of other regions.

Conclusions:

• A diverse spectrum of mutations, including those in coding and potentially noncoding regions of the CaSR gene, can lead to FHH.
• Mutations affecting the extracellular or transmembrane domains, as well as regulatory sequences, can disrupt CaSR structure and function, causing hypercalcemia.