A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia.
OBJECTIVE
Familial hypocalciuric hypercalcemia (FHH) syndrome is a rare benign condition, inherited as an autosomal dominant trait, in which inactivating mutations of the calcium-sensing receptor (CASR) gene affects the body's ability to regulate calcium homeostasis. Its outcome is featured by increased levels of serum calcium, moderate hypophosphatemia, and inadequately normal or elevated circulating parathyroid hormone levels. Affected patients are mostly asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroids.


METHODS
We evaluated for hypercalcemia an Italian family that was identified via a young adult male proband referred to our center for parathyroidectomy.


METHODS
The patients and the family members were evaluated both biochemically and genetically as suspected FHH subjects. An in vitro functional study was performed by site-directed mutagenesis, and CASR activity was monitored by measuring intracellular calcium ([Ca(2)(+)](i)).


RESULTS
The patient had a novel germline heterozygous CASR mutation (c.361_364GATT; p.D121del/fsX122). The mutation caused a premature stop codon at codon 122, exiting a truncated protein. The biochemical phenotype of all family members carrying the heterozygous deletion was concordant with classic FHH syndrome.


CONCLUSIONS
Our findings confirm the role of CASR gene mutational analysis to offer a valuable addition for the recognition of FHH in hypercalcemic patients not yet characterized for a positive familial history of hypercalcemia, the only condition that identifies CASR gene mutations in hypercalcemia.
Unit of Metabolic Bone Diseases, Department of Internal Medicine, University of Florence, Viale Morgagni 85, 50135 Florence, Italy.
Alberto
A
Falchetti
Alessia
A
Gozzini
Annalisa
A
Terranegra
Laura
L
Soldati
Giuseppe
G
Vezzoli
Gigliola
G
Leoncini
Francesca
F
Giusti
Francesco
F
Franceschelli
Laura
L
Masi
Annalisa
A
Tanini
Loredana
L
Cavalli
Maria Luisa
ML
Brandi
D000328:Adult; D018095:Germ-Line Mutation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D006934:Hypercalcemia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D007558:Italy; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*
C095550:CASR protein, human; D044169:Receptors, Calcium-Sensing