Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism
Michael R. Bowl,Samantha M. Mirczuk,Irina V. Grigorieva,Sian E. Piret,Treena Cranston,Lorraine Southam,Jeremy Allgrove,Jeremy Allgrove,Shailini Bahl,Caroline Brain,John Loughlin,John Loughlin,Zulf Mughal,Fiona Ryan,Nick Shaw,Yogini V. Thakker,Dov Tiosano,M. Andrew Nesbit,Rajesh V. Thakker +18 more
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TLDR
The results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor.Abstract:
GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor.read more
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Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target‐organ involvement, treatment, and challenges for future research
John P. Bilezikian,Aliya Khan,John T. Potts,Maria Luisa Brandi,Bart L. Clarke,Dolores M. Shoback,Harald Jüppner,Pierre D’Amour,John Fox,Lars Rejnmark,Leif Mosekilde,Mishaela R. Rubin,David W. Dempster,Rachel I Gafni,Michael T. Collins,Jim Sliney,James Sanders +16 more
TL;DR: This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease.
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Receptor-mediated endocytosis and endosomal acidification is impaired in proximal tubule epithelial cells of Dent disease patients
Caroline M Gorvin,Martijn J. Wilmer,Sian E. Piret,Brian Harding,L.P.W.J. van den Heuvel,L.P.W.J. van den Heuvel,O Wrong,Parmjit S. Jat,Jonathan D. Lippiat,Elena Levtchenko,Elena Levtchenko,Rajesh V. Thakker +11 more
TL;DR: It is demonstrated that Dent disease-causing CLC-5 mutations have differing effects on endosomal acidification and receptor-mediated endocytosis that may not be coupled.
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Calcium-Sensing Receptor Gene: Regulation of Expression.
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TL;DR: Functional cis-elements in the CASR promoters responsive to 1,25-dihydroxyvitamin D, proinflammatory cytokines, and the transcription factor glial cells missing-2 (GCM2) have been characterized.
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Transcription factors in parathyroid development: lessons from hypoparathyroid disorders
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Methylation profiling and evaluation of demethylating therapy in renal cell carcinoma
Christopher J. Ricketts,Mark R. Morris,Mark R. Morris,Dean Gentle,Salwati Shuib,Salwati Shuib,Michael D Brown,Noel W. Clarke,Wenbin Wei,Paul Nathan,Farida Latif,Eamonn R. Maher,Eamonn R. Maher +12 more
TL;DR: Preclinical evidence is provided that treatment with demethylating agents such as azacitidine might be useful for the treatment of advanced RCC and further insights into the role of epigenetic changes in the pathogenesis of RCC are provided.
References
More filters
Journal ArticleDOI
BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences.
TL;DR: 'BLAST 2 Sequences', a new BLAST-based tool for aligning two protein or nucleotide sequences, is described, utilizing the BLAST algorithm for pairwise DNA-DNA or protein-protein sequence comparison.
Journal ArticleDOI
On the topography of the genetic fine structure
TL;DR: In this paper, a detailed examination was made of the structure of a small portion of the genetic map of phage T4, the rII region, which controlled the ability of the phage to grow in Escherichia coli strain K, consists of two adjacent cistrons or functional units.
Journal ArticleDOI
Hyperparathyroid and hypoparathyroid disorders.
TL;DR: The four parathyroid glands, through the secretion ofParathyroid hormone, regulate serum calcium concentrations and bone metabolism, and high concentrations inhibit secretion by the par Kathyroid glands of parathy thyroid hormone and low concentrations stimulate it.
Journal ArticleDOI
Human Calcium-sensing Receptor Gene: VITAMIN D RESPONSE ELEMENTS IN PROMOTERS P1 AND P2 CONFER TRANSCRIPTIONAL RESPONSIVENESS TO 1,25-DIHYDROXYVITAMIN D
Lucie Canaff,Geoffrey N. Hendy +1 more
TL;DR: Functional VDREs have been identified in the CASR gene and provide the mechanism whereby 1,25(OH)2D up-regulates parathyroid, thyroid C-cell, and kidney CASR expression.
Journal ArticleDOI
Genetic ablation of parathyroid glands reveals another source of parathyroid hormone.
Thomas Günther,Zhou-Feng Chen,Jaesang Kim,Matthias Priemel,Johannes M. Rueger,Michael Amling,Jane M. Moseley,T. John Martin,David J. Anderson,Gerard Karsenty +9 more
TL;DR: Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands, and it is proposed that this backup mechanism may be a general feature of endocrine regulation.