Abstract
Context: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected hypercalcemic cohorts from a single center have not been reported. Objective: Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. Subjects: All were prospectively evaluated at the "Casa Sollievo della Sofferenza" Hospital in southern Italy over a 3-yr period. Methods: CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. Results: A single novel missense variant was identified in one PHPT case. However, in FHH probands, mutations were found in eight of 17 (47%). With a hypercalcemic family member, mutation detection rate in FHH rose to seven of eight (87%), whereas only one of nine sporadic cases was positive, and none of the three FIHP cases had detectable CASR mutations. Five missense variant CASRs, identified in control subjects, performed as wild type in functional assays, whereas the missense mutant CASRs identified in the FHH patients, and in the one PHPT case, exhibited significant impairment. A novel intronic mutation (IVS4-19a→c) found in one FHH family, created an abnormally spliced product in an in vitro minigene assay. Conclusion: CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states.
| Original language | English |
|---|---|
| Pages (from-to) | 1819-1829 |
| Number of pages | 11 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 95 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2010 |
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ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Endocrinology
- Biochemistry, medical
- Endocrinology, Diabetes and Metabolism
- Medicine(all)
Cite this
Calcium-Sensing Receptor (CASR) mutations in hypercalcemic states : Studies from a single endocrine clinic over three years. / Guarnieri, Vito; Canaff, Lucie; Yun, Francisco H J; Scillitani, Alfredo; Battista, Claudia; Muscarella, Lucia A.; Wong, Betty Y L; Notarangelo, Angelantonio; D'Agruma, Leonardo; Sacco, Michele; Cole, David E C; Hendy, Geoffrey N.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 4, 04.2010, p. 1819-1829.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Calcium-Sensing Receptor (CASR) mutations in hypercalcemic states
T2 - Studies from a single endocrine clinic over three years
AU - Guarnieri, Vito
AU - Canaff, Lucie
AU - Yun, Francisco H J
AU - Scillitani, Alfredo
AU - Battista, Claudia
AU - Muscarella, Lucia A.
AU - Wong, Betty Y L
AU - Notarangelo, Angelantonio
AU - D'Agruma, Leonardo
AU - Sacco, Michele
AU - Cole, David E C
AU - Hendy, Geoffrey N.
PY - 2010/4
Y1 - 2010/4
N2 - Context: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected hypercalcemic cohorts from a single center have not been reported. Objective: Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. Subjects: All were prospectively evaluated at the "Casa Sollievo della Sofferenza" Hospital in southern Italy over a 3-yr period. Methods: CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. Results: A single novel missense variant was identified in one PHPT case. However, in FHH probands, mutations were found in eight of 17 (47%). With a hypercalcemic family member, mutation detection rate in FHH rose to seven of eight (87%), whereas only one of nine sporadic cases was positive, and none of the three FIHP cases had detectable CASR mutations. Five missense variant CASRs, identified in control subjects, performed as wild type in functional assays, whereas the missense mutant CASRs identified in the FHH patients, and in the one PHPT case, exhibited significant impairment. A novel intronic mutation (IVS4-19a→c) found in one FHH family, created an abnormally spliced product in an in vitro minigene assay. Conclusion: CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states.
AB - Context: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected hypercalcemic cohorts from a single center have not been reported. Objective: Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. Subjects: All were prospectively evaluated at the "Casa Sollievo della Sofferenza" Hospital in southern Italy over a 3-yr period. Methods: CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. Results: A single novel missense variant was identified in one PHPT case. However, in FHH probands, mutations were found in eight of 17 (47%). With a hypercalcemic family member, mutation detection rate in FHH rose to seven of eight (87%), whereas only one of nine sporadic cases was positive, and none of the three FIHP cases had detectable CASR mutations. Five missense variant CASRs, identified in control subjects, performed as wild type in functional assays, whereas the missense mutant CASRs identified in the FHH patients, and in the one PHPT case, exhibited significant impairment. A novel intronic mutation (IVS4-19a→c) found in one FHH family, created an abnormally spliced product in an in vitro minigene assay. Conclusion: CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states.
UR - http://www.scopus.com/inward/record.url?scp=77951648285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951648285&partnerID=8YFLogxK
U2 - 10.1210/jc.2008-2430
DO - 10.1210/jc.2008-2430
M3 - Article
C2 - 20164288
AN - SCOPUS:77951648285
VL - 95
SP - 1819
EP - 1829
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 4
ER -