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Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism
  1. L Baumber1,
  2. C Tufarelli1,
  3. S Patel2,
  4. P King3,
  5. C A Johnson4,
  6. E R Maher4,
  7. R C Trembath1
  1. 1Division of Medical Genetics, Departments of Genetics and Cardiovascular Sciences, University of Leicester, Leicester, UK
  2. 2Leicestershire Genetics Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
  3. 3Derby Royal Infirmary, Derby, UK
  4. 4Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham Medical School, Birmingham, UK
  1. Correspondence to:
 Richard C Trembath
 Professor of Medical Genetics, Division of Medical Genetics, Departments of Genetics and Cardiovascular Sciences, University of Leicester, University Road, Leicester LE1 7RH, UK;

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Hypoparathyroidism is a heterogeneous group of disorders with both acquired and inherited causes, each presenting clinically with hypocalcaemia. Familial cases of hypoparathyroidism may be due to an isolated defect of the parathyroid glands or be a component of a syndrome disorder, examples of which include DiGeorge, hypoparathyroidism-retardation-dysmorphism, and Kenny-Caffey syndrome.1 Familial isolated hypoparathyroidism (FIH) is characterised by hypocalcaemia and hyperphosphataemia and may be due to an inherited deficiency or the abnormal activity of parathyroid hormone (PTH). FIH is heterogeneous with X linked, autosomal dominant, and autosomal recessive modes of inheritance reported.2 Mutations in the PTH gene on chromosome 11p have been described in both autosomal dominant and autosomal recessive forms of the disorder.3,4 Mature PTH is generated by cleavage of the signal peptide from the prepro-PTH, followed by successive proteolysis of pro-PTH within the Golgi apparatus.5 A requirement for normal PTH processing is emphasised by the detection of FIH disease causing mutations, which include two missense amino acid substitutions within the signal region of the prepro-PTH gene, leading to inefficient cleavage by signal peptidases.3,5

Heterozygous defects in the calcium sensing receptor (CASR) have been detected in autosomal dominant FIH and sporadic cases of hypoparathyroidism.6–8 All known CASR mutations in FIH lead to receptor activation.9,10 The CASR normally functions to provide a negative feedback loop, whereby binding of extracellular Ca2+ activates the receptor, resulting in decreased PTH secretion by parathyroid cells, but also through inhibition of calcium reabsorption in the renal distal tubule. Constitutive activation of this receptor therefore results in hypocalcaemia and hypercalciuria.

Notwithstanding these reports, the molecular genetic basis of most cases of autosomal recessive FIH remains unknown.1 Recently, a homozygous deletion within the human GCM2 (glial cells missing, Drosophila homologue B, previously referred to …

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  • This work was supported by a Wellcome Trust grant (programme grant 062346/Z/00/Z, Functional Genomics National Autozygosity Mapping Resource). CT is a Royal Society Dorothy Hodgkin Research Fellow.

  • Competing interests: none declared

  • Ethics approval: approval was obtained from the Leicestershire research ethics committee.