Alternative titles; symbols
ORPHA: 101049, 405; DO: 0060701;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | Hypocalciuric hypercalcemia, type II | 145981 | Autosomal dominant | 3 | GNA11 | 139313 |
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.
Familial hypocalciuric hypercalcemia type II (HHC2) is an autosomal dominant disorder characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion and normal circulating parathyroid hormone concentrations in most patients. Patients are generally asymptomatic (summary by Nesbit et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980).
Gorvin et al. (2016) reported a 65-year-old woman of Indian origin with poor mobility and recurrent falls. She had hypercalcemia and a low urinary calcium-to-creatinine clearance ratio; serum phosphate, creatinine, PTH, and 25-hydroxyvitamin D levels were normal. There was no family history of hypercalcemia, but relatives were not available for evaluation.
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.
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.
In a 65-year-old woman of Indian origin with hypocalciuric hypercalcemia, who was negative for mutation in the CASR and AP2S1 genes, Gorvin et al. (2016) sequenced exons and adjacent splice sites of the GNA11 gene and identified heterozygosity for a missense mutation (T54M; 139313.0008). Family members were unavailable for segregation analysis. Functional studies demonstrated impairment of Ca(2+)-channel signaling with the mutant protein.
Gorvin, C. M., Cranston, T., Hannan, F. M., Rust, N., Qureshi, A., Nesbit, M. A., Thakker, R. V. A G-protein subunit-alpha11 loss-of-function mutation, thr54met, causes familial hypocalciuric hypercalcemia type 2 (FHH2). J. Bone Miner. Res. 31: 1200-1206, 2016. [PubMed: 26729423] [Full Text: https://doi.org/10.1002/jbmr.2778]
Heath, H., III, Jackson, C. E., Otterud, B., Leppert, M. F. Familial benign hypercalcemia (FBH) phenotype results from mutations at two distinct loci on chromosomes 3q and 19p. (Abstract) Clin. Res. 41: 270A only, 1993.
Heath, H., III, Leppert, M. F., Lifton, R. P., Penniston, J. T. Genetic linkage analysis in familial benign hypercalcemia using a candidate gene strategy. I: Studies in four families. J. Clin. Endocr. Metab. 75: 846-851, 1992. [PubMed: 1517376] [Full Text: https://doi.org/10.1210/jcem.75.3.1517376]
Nesbit, M. A., Hannan, F. M., Howles, S. A., Babinsky, V. N., Head, R. A., Cranston, T., Rust, N., Hobbs, M. R., Heath, H., III, Thakker, R. V. Mutations affecting G-protein subunit alpha-11 in hypercalcemia and hypocalcemia. New Eng. J. Med. 368: 2476-2486, 2013. [PubMed: 23802516] [Full Text: https://doi.org/10.1056/NEJMoa1300253]