Autosomal dominant
hypocalcemia (ADH) caused by activating mutations of
calcium-sensing receptor (CaSR) is characterized by
hypocalcemia with inappropriately low concentration of PTH and relative
hypercalciuria. Active
vitamin D treatment often leads to
nephrolithiasis and renal impairment in patients with ADH. However, differential diagnosis between ADH and
idiopathic hypoparathyroidism is sometimes very difficult. Here, we report a mutation of CaSR and its functional property found in three generations of a Japanese family. The proband developed
seizures at 7 days of age. His mother and elder sister were discovered to have
hypoparathyroidism by family survey, but his father was normocalcemic. His grandfather developed
heart failure and was found to have
hypoparathyroidism. All affected members had been treated with active
vitamin D3 and bilateral
nephrolithiasis were detected in three of them.
DNA sequencing revealed that all affected patients had a heterozygous mutation in CaSR gene that causes
proline to
leucine substitution at
codon 221 (P221L). In vitro functional analysis of the mutant CaSR by measuring
inositol 1,4,5-trisphosphate production in response to changes of extracellular Ca indicated that this mutation is an activating one and responsible for ADH in this family. Therefore, careful monitoring of urinary Ca excretion before and during treatment of PTH-deficient
hypoparathyroidism is very important, and screening of CaSR mutation should be considered in patients with relative
hypercalciuria or with a family history of
hypocalcemia.