Endocrine Abstracts (2006) 11 P534

Novel inactivating mutations in four Italian cases of familial hypocalciuric hypercalcemia

F Cetani, S Borsari, M Lemmi, E Pardi, E Ambrogini, A Pinchera & C Marcocci

Department of Endocrinology, University of Pisa, Pisa, Italy.

Familial Hypocalciuric Hypercalcemia (FHH) is an autosomal dominant disorder characterized by moderate and lifelong hypercalcemia, relative hypocalciuria, and inappropriately normal serum PTH levels. Loss-of-function mutation of the CaR are responsible for this disease.

In this study we describe three unrelated Italian kindreds (A, B and C) and one patient with FHH. The diagnosis of FHH in the propositus was suspected on the finding of hypercalcemia, normal serum, and calcium clearance/creatinine clearance ratio <0.01. Genetic analysis of the CaR gene was carried out by polymerase chain reaction amplification and DNA sequencing of exons 2–7, which include the entire coding region and flanking exon-intron boundaries of the gene. The region of interest detected in the probands was also amplified in the family members and in 50 unrelated healthy subjects. In family A, genetic analysis of CaR revealed a novel heterozygous missense mutation (C→T) in exon 7 leading to a substitution of histidine for tyrosine at codon 595 (H595Y) in extracellular domain of CaR. The same mutation was identified in affected family members (sister’s and father’s proband). In family B, a heterozygous mutation was found in the proband at codon 748 with a substitution of C→A in exon 7, leading to conversion of proline to histidine.The same mutation was identified in the affected son. This mutation is located in the second extracellular loop. In family C, nucleotide sequencing revealed that the proband had a novel heterozygous mutation substituting cysteine for tryptophan at codon 765 (C765W). The absence of three mutations in 50 unrelated healtly subjects could exclude their polymorphic nature. In last case, direct sequencing showed a substitution of G to C in the donor splice site of intron 2 (IVS2+1G>C).

In conclusion, we describe three unrelated Italian cases of FHH with a loss of function mutation of CaR. Two are missense and located in the extracellular domain, one is located in intracellular domain and one is a splice site mutation.

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