Novel mutations in the calcium sensing receptor gene: a case series — ASN Events
  1. Schedule
  2. Poster Viewing II (even numbers)
  3. Novel mutations in the calcium sensing receptor gene: a case series

Novel mutations in the calcium sensing receptor gene: a case series (#166)

Aaron M Hawkins 1 2 , Deepak L Vardesh 1 2 , Kavitha A Razak 1 2 , Valentine J Hyland 3 , Rick V Jackson 1 2
  1. Department of Medicine, Logan Hospital, Meadowbrook, QLD, Australia
  2. School of Medicine, Griffith University, Gold Coast, Queensland, Australia
  3. Molecular Genetics Laboratory, Pathology Queensland, Brisbane, QLD, Australia

Introduction

The Calcium Sensing Receptor (CASR) plays a crucial role in serum calcium homeostasis [1]. Inactivating mutations cause Hypercalcaemia[2] and activating mutations Hypocalcaemia[3]. It is important to consider these in patients with serum calcium abnormalities to avoid potentially harmful and unnecessary investigations and treatment. We present three novel mutations in the CASR gene.

Cases

Two female patients aged 29 and 48 years with asymptomatic hypercalcaemia were extensively investigated. The findings of normal parathyroid imaging and low urine calcium levels prompted genetic testing for Familial Hypocalciuric Hypercalcaemia. Genetic sequencing revealed novel inactivating point mutations in the CASR gene located at c.[1023G>T] p.[Lys341Asn] and c.[610T>A] p.[Phe204Ile] respectively. These mutations are previously unreported and consistent with inactivating mutations [4].

A 63 year old female with asymptomatic hypocalcaemia was investigated. Normal investigations including parathyroid imaging prompted suspicion for Autosomal Dominant Hypocalcaemia. Genetic sequencing revealed a novel missense mutation in exon 7 causing a Phenylalanine to Serine amino-acid change c.[2462T>C] p.[Phe821Ser], consistent with an activating mutation of the CASR gene [4].

58b4d3ee5374e-CASR+Mutations+Table.jpg

Method

Bi-directional Sanger sequencing of PCR amplified genomic DNA encompassing CASR exons 2 – 7. CASR gene reference sequence NM_000388.3 was used.

 

Discussion

The CASR is a G-protein-coupled receptor which consists of an extracellular component that senses the external calcium level and transmembrane and intracellular domains that are involved in the signal transduction and subsequent effect on the target cells [5].

A previous case reported a different amino acid substitution in the same location as case 3 but with a more severe phenotype [6]. We hypothesise that this is due to the substitution of leucine for phenylalanine resulting in a more profound conformational or functional change to the receptor than the serine substitution.

These cases highlight the importance of considering CASR mutations in hypocalcaemia and hypercalcaemia.

  1. Hoenderop JG, Nilius B, Bindels RJ: Calcium absorption across epithelia. Physiol Rev 2005, 85(1):373-422
  2. Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 1994, 8(3):303-307.
  3. Pollak MR, Brown EM, Chou Y-HW, Hebert SC, Marx SJ, Stelnmann B, Levi T, Seidman CE, Seidman JG: Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993, 75(7):1297-1303.
  4. CASRdb (the Calcium Sensing Receptor Database). [http://www.casrdb.mcgill.ca/] (accessed 27 Febuary 2017)
  5. Brown EM: Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 2007, 3(2):122-133.
  6. Shiohara M, Mori T, Mei B, Brown EM, Watanabe T, Yasuda T: A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism. Eur J Pediatr 2004, 163(2):94-98.