CASR gene activating mutations in two families with autosomal dominant hypocalcemia.
BACKGROUND
Autosomal dominant hypocalcemia (ADH) is an endocrine disorder caused by activating mutations of the calcium-sensing receptor (CASR) gene which plays a major role in maintaining calcium homeostasis. Biochemical features of ADH are hypocalcemia and hypercalciuria with inappropriately low levels of parathyroid hormone (PTH). We report on two four-generation families affected by ADH.


OBJECTIVE
To identify mutations of CASR gene in subjects affected by familial idiopathic hypoparathyroidism. To perform functional assays of identified CASR variants by transient transfection on HEK293 cells.


RESULTS
We identified two CASR variants (Q681R and P221L): the Q681R variant was novel while the P221L had been previously published. Functional assays on the Q681R variant showed that it did not alter the whole expression nor the correct plasmamembrane localization, but enhanced the signaling function, increasing the sensitivity of the receptor as compared to the WT.


CONCLUSIONS
We report two activating CASR mutations in two families affected by ADH and the functional assays performed on the novel variant Q681R. Our work enlarged the spectrum of mutations of the CASR and contributed to a better elucidation of the protein function.
Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, viale Padre Pio, 71013 San Giovanni Rotondo, FG, Italy. v.guarnieri@operapadrepio.it
Vito
V
Guarnieri
Angela
A
Valentina D'Elia
Filomena
F
Baorda
Valerio
V
Pazienza
Giorgia
G
Benegiamo
Pietro
P
Stanziale
Massimiliano
M
Copetti
Claudia
C
Battista
Franco
F
Grimaldi
Giuseppe
G
Damante
Fabio
F
Pellegrini
Leonardo
L
D'Agruma
Leopoldo
L
Zelante
Massimo
M
Carella
Alfredo
A
Scillitani
D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004252:DNA Mutational Analysis; D005260:Female; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics* / Q000378:metabolism; D006996:Hypocalcemia / Q000235:genetics* / Q000378:metabolism; D007011:Hypoparathyroidism / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010281:Parathyroid Hormone / Q000172:deficiency*; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
C095550:CASR protein, human; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium