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J Pediatr Genet 2015; 04(01): 029-033
DOI: 10.1055/s-0035-1554979
Case Report
Georg Thieme Verlag KG Stuttgart · New York

Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia

Joana Regala
1   Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal
,
Branca Cavaco
2   Molecular Pathobiology Research Centre, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal
3   Chronic Diseases Research Center, NOVA Medical School, NOVA University of Lisbon, Lisbon, Portugal
,
Rita Domingues
2   Molecular Pathobiology Research Centre, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal
3   Chronic Diseases Research Center, NOVA Medical School, NOVA University of Lisbon, Lisbon, Portugal
,
Catarina Limbert
1   Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal
,
Lurdes Lopes
1   Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal
› Author Affiliations
Further Information

Publication History

16 October 2014

08 December 2014

Publication Date:
17 July 2015 (online)

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Abstract

Autosomal dominant hypocalcemia, caused by activating mutations of the calcium-sensing receptor (CASR) gene, is characterized by hypocalcemia with an inappropriately low concentration of parathyroid hormone (PTH). In this report, we describe the identification of a novel missense mutation in the CASR gene, in a boy with autosomal dominant hypocalcemia. Polymerase chain reaction (PCR)–single strand and DNA sequencing revealed a heterozygous mutation in CASR gene that causes a leucine substitution for serine at codon 123 (p.Leu123Ser). This mutation was absent in DNA from 50 control patients. In silico studies suggest that the identified variant was likely pathogenic. Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected. Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later, namely, hand tremor and rigidity at the age of 7 and 18 years, respectively. Laboratory analysis revealed hypocalcemia, hyperphosphatemia, and low-serum PTH with hypomagnesemia and mild hypercalciuria. After 2 years of treatment with calcium supplements and calcitriol, some brief periods of clinical improvement were reported; as well as an absence of nephrocalcinosis.

Keywords

autosomal dominant hypocalcemia - calcium-sensing receptor - missense mutation - mosaicism
 

  • References

  • 1 Hannan FM, Thakker RV. Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract Res Clin Endocrinol Metab 2013; 27 (3) 359-371
    CrossrefPubMedSearch in Google Scholar
  • 2 Aida K, Koishi S, Tawata M, Onaya T. Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney. Biochem Biophys Res Commun 1995; 214 (2) 524-529
    CrossrefPubMedSearch in Google Scholar
  • 3 Garrett JE, Tamir H, Kifor O , et al. Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene. Endocrinology 1995; 136 (11) 5202-5211
    PubMedSearch in Google Scholar
  • 4 Kapoor A, Satishchandra P, Ratnapriya R , et al. An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol 2008; 64 (2) 158-167
    CrossrefPubMedSearch in Google Scholar
  • 5 D'Souza-Li L. The calcium-sensing receptor and related diseases. Arq Bras Endocrinol Metabol 2006; 50 (4) 628-639
    CrossrefPubMedSearch in Google Scholar
  • 6 Lienhardt A, Garabédian M, Bai M , et al. A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia. J Clin Endocrinol Metab 2000; 85 (4) 1695-1702
    CrossrefPubMedSearch in Google Scholar
  • 7 Nesbit MA, Hannan FM, Howles SA , et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med 2013; 368 (26) 2476-2486
    CrossrefPubMedSearch in Google Scholar
  • 8 Chikatsu N, Watanabe S, Takeuchi Y , et al. A family of autosomal dominant hypocalcemia with an activating mutation of calcium-sensing receptor gene. Endocr J 2003; 50 (1) 91-96
    CrossrefPubMedSearch in Google Scholar
  • 9 Aggarwal S, Kailash S, Sagar R , et al. Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium. Eur J Endocrinol 2013; 168 (6) 895-903
    CrossrefPubMedSearch in Google Scholar
  • 10 Maret A, Ding C, Kornfield SL, Levine MA. Analysis of the GCM2 gene in isolated hypoparathyroidism: a molecular and biochemical study. J Clin Endocrinol Metab 2008; 93 (4) 1426-1432
    CrossrefPubMedSearch in Google Scholar
  • 11 Ertl DA, Stary S, Streubel B, Raimann A, Haeusler G. A novel homozygous mutation in the parathyroid hormone gene (PTH) in a girl with isolated hypoparathyroidism. Bone 2012; 51 (3) 629-632
    CrossrefPubMedSearch in Google Scholar
  • 12 Kifor O, McElduff A, LeBoff MS , et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004; 89 (2) 548-556
    CrossrefPubMedSearch in Google Scholar
  • 13 Yamamoto M, Akatsu T, Nagase T, Ogata E. Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders?. J Clin Endocrinol Metab 2000; 85 (12) 4583-4591
    CrossrefPubMedSearch in Google Scholar
  • 14 Calcium-sensing receptor database. Search mutations: geno/phenotype search. Available at: http://www.casrdb.mcgill.ca/?Topic=MutationSearch . Accessed October 15, 2014
    PubMed
  • 15 Hannan FM, Nesbit MA, Zhang C , et al. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet 2012; 21 (12) 2768-2778
    CrossrefPubMedSearch in Google Scholar
  • 16 Jiang Y, Minet E, Zhang Z, Silver PA, Bai M. Modulation of interprotomer relationships is important for activation of dimeric calcium-sensing receptor. J Biol Chem 2004; 279 (14) 14147-14156
    CrossrefPubMedSearch in Google Scholar
  • 17 Huang Y, Zhou Y, Yang W , et al. Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem 2007; 282 (26) 19000-19010
    CrossrefPubMedSearch in Google Scholar
  • 18 Vargas-Poussou R, Huang C, Hulin P , et al. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol 2002; 13 (9) 2259-2266
    CrossrefPubMedSearch in Google Scholar
  • 19 Sato K, Hasegawa Y, Nakae J , et al. Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. J Clin Endocrinol Metab 2002; 87 (7) 3068-3073
    CrossrefPubMedSearch in Google Scholar
  • 20 Cole DE, Yun FH, Wong BY , et al. Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. J Mol Endocrinol 2009; 42 (4) 331-339
    PubMedSearch in Google Scholar
  • 21 Hendy GN, Minutti C, Canaff L , et al. Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene. J Clin Endocrinol Metab 2003; 88 (8) 3674-3681
    CrossrefPubMedSearch in Google Scholar
  • 22 Smits M, Gabreëls F, Froeling P , et al. Autosomal dominant idiopathic hypoparathyroidism and nervous system dysfunction: report of three cases and review of the literature. J Neurol 1982; 228 (2) 113-122
    CrossrefPubMedSearch in Google Scholar
  • 23 Raue F, Pichl J, Dörr HG , et al. Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey. Clin Endocrinol (Oxf) 2011; 75 (6) 760-765
    CrossrefPubMedSearch in Google Scholar
  • 24 Tambyah PA, Ong BK, Lee KO. Reversible parkinsonism and asymptomatic hypocalcemia with basal ganglia calcification from hypoparathyroidism 26 years after thyroid surgery. Am J Med 1993; 94 (4) 444-445
    CrossrefPubMedSearch in Google Scholar
  • 25 Egbuna OI, Brown EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008; 22 (1) 129-148
    CrossrefPubMedSearch in Google Scholar
  • 26 Winer KK, Ko CW, Reynolds JC , et al. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab 2003; 88 (9) 4214-4220
    CrossrefPubMedSearch in Google Scholar
  • 27 Letz S, Rus R, Haag C , et al. Novel activating mutations of the calcium-sensing receptor: the calcilytic NPS-2143 mitigates excessive signal transduction of mutant receptors. J Clin Endocrinol Metab 2010; 95 (10) E229-E233
    CrossrefPubMedSearch in Google Scholar
  • 28 Park SY, Mun HC, Eom YS , et al. Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914. Clin Endocrinol (Oxf) 2013; 78 (5) 687-693
    CrossrefPubMedSearch in Google Scholar