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Title: Novel mutations associated with inherited human calcium-sensing receptor disorders: A clinical genetic study
Authors: García-Castaño, Alejandro
Madariaga, Leire
Pérez de Nanclares, Gustavo
Ariceta, Gema
Gaztambide, Sonia
Castaño, Luis
Ramírez González, Juan Andrés 
Gómez Cabrera, María Milagrosa 
Montalban, C
Ruiz, R
Socias, C
Boronat Cortés, Mauro 
Aparicio, C
Alonso Bilbao, Ignacio 
Conde, S
Garcia-Cuartero, B
Jimenez, B
Medina Rodríguez, Pedro
Perez, E
Hidalgo-Barquero, E
Barrio, R
Gonzalez, CM
Cordo, CLR
Cruz, J
Hernandez, J
Fernández-Ramos, C
Marti, J
Clemente, M
Garcia, L
Rica, I
Martinez, R
Urrutia, I
de LaPiscina, IM
Santos, F
Gil-Pena, H
Coto, E
Loredo, V
Ordonez, FA
Rodriguez, J
Riera, EB
Hernandez, O
Fuente, R
Claramunt, D
Nieto, VMG
Martin, FC
Acosta, HG
Trujillo, ER
Yanes, MIL
Lanus, EC
Castano, L
Madariaga, L
de Nanclares, GP
Garcia-Castano, A
Aguirre, M
Campos Herrero Navas,María Isolina 
Aguayo, A
Ariceta, G
Meseguer, A
Boronat M
Issue Date: 2019
Journal: European Journal of Endocrinology 
Abstract: Objective: Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described. Methods: The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing. Results: Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally hig h parathyroid hormone (PTH) levels (median: 52 pg/ mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypo parathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no othe r alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup). Conclusions: Patients with CASR mutations may not fit the classic clinical pictures of hypercal cemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are impo rtant for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorde rs in 82 patients in the study cohort.
ISSN: 0804-4643
DOI: 10.1530/EJE-18-0129
Source: European Journal of Endocrinology [ISSN 0804-4643], v. 180 (1), p. 59-70, (Enero 2019)
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