Hypocalciuric Hypercalcemia, Familial, Type Ii

A number sign (#) is used with this entry because of evidence that familial hypocalciuric hypercalcemia type II (HHC2) is caused by heterozygous mutation in the GNA11 gene (139313) on chromosome 19p13.

For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980).

Mapping

In a family with hypocalciuric hypercalcemia in which linkage to 3q had been excluded (kindred 11675), Heath et al. (1992) and Heath et al. (1993) demonstrated linkage to 19p13.2, obtaining a 2-point lod score of 3.70 (theta = 0.001) at D19S266 and a lod score of 3.44 at D19S20.

Molecular Genetics

In the proband from a 4-generation kindred with hypocalciuric hypercalcemia, previously studied by Heath et al. (1992) (kindred 11675), and 9 unrelated patients with familial HHC who were known to be negative for mutations in the HHC-associated genes CASR (601199) and AP2S1 (602242), Nesbit et al. (2013) sequenced the candidate gene GNA11. In the proband from kindred 11675, they identified a heterozygous 3-bp deletion (139313.0001) that was confirmed to segregate with disease in the family; in addition, 1 of the 9 unrelated patients with HHC was found to be heterozygous for a missense mutation (L135Q; 139313.0002). Functional analysis in HEK293 cells stably expressing calcium-sensing receptors demonstrated that the mutant GNA11 proteins induce a decrease in sensitivity to changes in extracellular calcium concentrations.