title: GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts.
abstract: The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.
authors.affiliation: Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, GermanyCenter for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité University Medicine Berlin, Berlin, GermanyDivision of Paediatric Endocrinology and DiabetesDepartment of Paediatrics, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mayr
authors.affiliation: Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, GermanyCenter for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité University Medicine Berlin, Berlin, GermanyDivision of Paediatric Endocrinology and DiabetesDepartment of Paediatrics, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.affiliation: Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, GermanyCenter for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité University Medicine Berlin, Berlin, GermanyDivision of Paediatric Endocrinology and DiabetesDepartment of Paediatrics, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Helmuth-Günther
authors.initials: HG
authors.lastname: Dörr
authors.affiliation: Division of Endocrinology and DiabetesDepartment of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, GermanyCenter for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charité University Medicine Berlin, Berlin, GermanyDivision of Paediatric Endocrinology and DiabetesDepartment of Paediatrics, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany christof.schoefl@uk-erlangen.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Schöfl
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000235:genetics; D006961:Hyperparathyroidism / Q000188:drug therapy* / Q000235:genetics; D006996:Hypocalcemia / Q000188:drug therapy* / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000235:genetics*
chemical_list: C510065:AP2S1 protein, human; D033962:Adaptor Protein Complex 2; D034002:Adaptor Protein Complex sigma Subunits; C095550:CASR protein, human; C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits; D044169:Receptors, Calcium-Sensing