SFEBES2007 Poster Presentations Growth and development (10 abstracts)
Characterisation of parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) in 3 families with autosomal recessive hypoparathyroidism
Michael Bowl 1 , Samantha Mirczuk 1 , Lorraine Southam 2 , Zulf Mughal 3 , Fiona Ryan 4 , Nick Shaw 5 , Elaine Tham 6 , Ze’ev Hochberg 7 , Dov Tiosano 7 , John Loughlin 2 , M Andrew Nesbit 1 & Rajesh Thakker 1
1Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and metabolism, Churchill Hospital, Oxford, United Kingdom; 2Institute of Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, United Kingdom; 3Department of Paediatrics, Saint Mary’s Hospital for Women and Children, Manchester, United Kingdom; 4Paediatric Department, The John Radcliffe Hospital, Oxford, United Kingdom; 5Birmingham Children’s Hospital, Birmingham, United Kingdom; 6Endocrinology & Diabetes Unit, British Columbia’s Children’s Hospital, Vancouver, Canada; 7Rambam Medical Center, Department of Pediatrics, Division of Endocrinology, Haifa, Israel.
GCMB, which is the mammalian homologue of the Drosophila gene Glial cells missing, encodes a 506 amino acid parathyroid-specific transcription factor that contains: a DNA-binding domain at residues 21–174; a predicted nuclear localization signal at residues 176–193; an inhibitory domain at residues 258–347; and two transactivation domains at residues 174–263, and residues 428–506. Mutations of GCMB, which is located on chromosome 6p23–24 and comprises 5 exons, have been previously reported in only 3 families with autosomal recessive hypoparathyroidism. We ascertained 9 affected and 13 unaffected individuals from 6 families, whose origins were from the Indian subcontinent or Middle-East, with autosomal recessive hypoparathyroidism and have investigated them for GCMB mutations. Venous blood was collected after obtaining informed consent, using guidelines approved by the local ethical committee. Leukocyte DNA was extracted and used with GCMB-specific primers for PCR amplification of the five exons. DNA sequence analysis of the PCR products revealed the occurrence of two different homozygous mutations, consisting of a missense mutation, Arg47Leu, in one Indian family and a frameshifting deletion involving a single nucleotide (ATC to A_C) at codon 298 in two families from Western Kashmir. Haplotype analysis using the 5 polymorphic microsatellite loci 6pter–D6S470, GCMB, D6S1721, D6S1006, D6S1653, D6S289−6pcen from chromosome 6p23–24 revealed that these two families are unrelated. The Arg47Leu is located within the DNA-binding domain of the protein and has previously been shown to abolish DNA binding ability. The frameshift deletion predicts the occurrence of 9 missense amino acids followed by a premature termination signal at codon 307, which would disrupt the inhibitory and second transactivation domains. Thus, our studies which have identified 3 additional families with autosomal recessive hypoparathyroidism due to GCMB mutations, indicate that GCMB mutations may be responsible for 50% of autosomal recessive hypoparathyroidism.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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