Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype.
BACKGROUND
Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.


METHODS
A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients' phenotype, age of disease manifestation and mode of inheritance.


RESULTS
All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients' clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients' serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH.


CONCLUSIONS
There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.
Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Erlangen, Germany.
Markus
M
Glaudo
Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Erlangen, Germany.
Saskia
S
Letz
Endokrinologie in CharlottenburgBerlin, Germany.
Marcus
M
Quinkler
Endokrinologie in CharlottenburgBerlin, Germany.
Ulrich
U
Bogner
Department of EndocrinologyDiabetes and Nutrition.
Ulf
U
Elbelt
Department of EndocrinologyDiabetes and Nutrition.
Christian J
CJ
Strasburger
Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Dirk
D
Schnabel
Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Erwin
E
Lankes
Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany.
Sandra
S
Scheel
Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany.
Joachim
J
Feldkamp
Endocrine PracticeHeidelberg, Germany.
Christine
C
Haag
Endocrine PracticeHeidelberg, Germany.
Egbert
E
Schulze
Endocrine PracticeHeidelberg, Germany.
Karin
K
Frank-Raue
Endocrine PracticeHeidelberg, Germany.
Friedhelm
F
Raue
Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Erlangen, Germany bernhard.mayr@uk-erlangen.de.
Bernhard
B
Mayr
Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Erlangen, Germany.
Christof
C
Schöfl
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006961:Hyperparathyroidism / Q000151:congenital / Q000235:genetics*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000235:genetics*
C095550:CASR protein, human; D044169:Receptors, Calcium-Sensing; D002118:Calcium