title: Novel calcium-sensing receptor cytoplasmic tail deletion mutation causing autosomal dominant hypocalcemia: molecular and clinical study.
abstract: OBJECTIVE
  Autosomal dominant hypocalcemia (ADH) is a rare disorder caused by activating mutations of the calcium-sensing receptor (CASR). The treatment of ADH patients with 1α-hydroxylated vitamin D derivatives can cause hypercalciuria leading to nephrocalcinosis.
  
  
  METHODS
  We studied a girl who presented with hypoparathyroidism and asymptomatic hypocalcemia at age 2.5 years. Mutations of CASR were investigated by DNA sequencing. Functional analyses of mutant and WT CASRs were done in transiently transfected human embryonic kidney (HEK293) cells.
  
  
  RESULTS
  The proband and her father are heterozygous for an eight-nucleotide deletion c.2703_2710delCCTTGGAG in the CASR encoding the intracellular domain of the protein. Transient expression of CASR constructs in kidney cells in vitro suggested greater cell surface expression of the mutant receptor with a left-shifted extracellular calcium dose-response curve relative to that of the WT receptor consistent with gain of function. Initial treatment of the patient with calcitriol led to increased urinary calcium excretion. Evaluation for mosaicism in the paternal grandparents of the proband was negative.
  
  
  CONCLUSIONS
  We describe a novel naturally occurring deletion mutation within the CASR that apparently arose de novo in the father of the ADH proband. Functional analysis suggests that the cytoplasmic tail of the CASR contains determinants that regulate the attenuation of signal transduction. Early molecular analysis of the CASR gene in patients with isolated idiopathic hypoparathyroidism is recommended because of its relevance to clinical outcome and treatment choice. In ADH patients, calcium supplementation and low-dose cholecalciferol avoids hypocalcemic symptoms without compromising renal function.
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1 geoffrey.hendy@mcgill.ca obermannova@seznam.cz.
authors.forename: Barbora
authors.initials: B
authors.lastname: Obermannova
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Sumnik
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1.
authors.forename: Petra
authors.initials: P
authors.lastname: Dusatkova
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Cinek
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1.
authors.forename: Michael
authors.initials: M
authors.lastname: Grant
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1 Department of PediatricsSecond Faculty of Medicine, Charles University in Prague, University Hospital Motol V Uvalu 84, CZ-150 06 Prague, Czech RepublicLady Davis Institute for Medical ResearchSMBD-Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2Experimental Therapeutics and MetabolismRoom No. EM1.3226 RI-McGill University Health Centre Glen Site, 1001 Décarie Boulevard, Montréal, Québec, Canada H4A 3J1Departments of MedicinePhysiology, and Human Genetics, McGill University, Montréal, Québec, Canada H4A 3J1 geoffrey.hendy@mcgill.ca obermannova@seznam.cz.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
mesh_terms: D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D003593:Cytoplasm; D005190:Family; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics* / Q000473:pathology; D006996:Hypocalcemia / Q000235:genetics* / Q000473:pathology; D007011:Hypoparathyroidism / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D008297:Male; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D044169:Receptors, Calcium-Sensing