PMID- 19789209 OWN - NLM STAT- MEDLINE DCOM- 20100107 LR - 20211020 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 94 IP - 11 DP - 2009 Nov TI - A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. PG - 4372-9 LID - 10.1210/jc.2008-2484 [doi] AB - CONTEXT: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism. OBJECTIVE: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred. DESIGN: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR. RESULTS: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband's parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR. CONCLUSION: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions. FAU - Lietman, Steven A AU - Lietman SA AD - Departments of Orthopaedic Surgery, Cleveland Clinic Lerner Research Institute and Foundation, Cleveland, Ohio 44195, USA. lietmas@ccf.org FAU - Tenenbaum-Rakover, Yardena AU - Tenenbaum-Rakover Y FAU - Jap, Tjin Shing AU - Jap TS FAU - Yi-Chi, Wu AU - Yi-Chi W FAU - De-Ming, Yang AU - De-Ming Y FAU - Ding, Changlin AU - Ding C FAU - Kussiny, Najat AU - Kussiny N FAU - Levine, Michael A AU - Levine MA LA - eng PT - Case Reports PT - Journal Article DEP - 20090929 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Parathyroid Hormone) RN - 0 (Receptors, Calcium-Sensing) RN - 0RH81L854J (Glutamine) RN - 94ZLA3W45F (Arginine) RN - SY7Q814VUP (Calcium) SB - IM MH - Amino Acid Substitution MH - Arginine/genetics MH - Calcium/blood MH - Cell Line MH - Child, Preschool MH - Chromosome Disorders/genetics MH - Exons/genetics MH - Female MH - Gene Silencing MH - Genes, Recessive/*genetics MH - Glutamine/genetics MH - Heterozygote MH - Humans MH - Hypercalcemia/complications/*genetics MH - Hypercalciuria/complications/*genetics MH - Male MH - *Mutation MH - Parathyroid Hormone/blood MH - Pedigree MH - Receptors, Calcium-Sensing/*genetics MH - Transfection PMC - PMC2775658 EDAT- 2009/10/01 06:00 MHDA- 2010/01/08 06:00 PMCR- 2010/11/01 CRDT- 2009/10/01 06:00 PHST- 2009/10/01 06:00 [entrez] PHST- 2009/10/01 06:00 [pubmed] PHST- 2010/01/08 06:00 [medline] PHST- 2010/11/01 00:00 [pmc-release] AID - jc.2008-2484 [pii] AID - 6836 [pii] AID - 10.1210/jc.2008-2484 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2009 Nov;94(11):4372-9. doi: 10.1210/jc.2008-2484. Epub 2009 Sep 29.