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      Mutations in Nicotinamide Nucleotide Transhydrogenase (NNT) cause familial glucocorticoid deficiency

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          Abstract

          Using targeted exome sequencing we identified mutations in NNT, an antioxidant defence gene, in patients with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased ROS levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.

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          Most cited references12

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          A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice.

          C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close KATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.
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            Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency.

            Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. The study design comprised single-nucleotide polymorphism genotyping and mutation detection. The study was conducted at secondary and tertiary referral centers. Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. There were no interventions. Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD.
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              Applications of a rat multiple tissue gene expression data set.

              With the sequencing and assembly of the rat genome comes the difficult task of assigning functions to genes. Tissue localization of gene expression gives some information about the potential role of a gene in physiology. Various examples of the utility of multiple tissue gene expression data sets are illustrated here. First, we highlight their use in finding genes that might play an important role in a particular tissue on the basis of exclusive expression in that tissue or coexpression with a gene or genes with known function. Second, we show how this data might be used to explain known phenotypic differences between strains. Third, we show how expression patterns of genes in a genomic interval might identify candidate genes in quantitative trait loci (QTL) mapping studies. Lastly, we show how multiple tissue and species data can help researchers prioritize follow up studies to microarray experiments. All of these applications of multiple tissue gene expression data sets will play a role in functionally annotating the rat genome.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                9 May 2012
                27 May 2012
                01 January 2013
                : 44
                : 7
                : 740-742
                Affiliations
                [1 ]Queen Mary University of London, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK
                [2 ]ATLAS Biolabs GmbH Friedrichstraße 147 10117 Berlin, Germany
                [3 ]Cologne Center for Genomics (CCG), University of Cologne, Weyertal 115b, 50931 Köln, Germany
                [4 ]Royal Berkshire Hospital, London Road, Reading, Berkshire UK
                [5 ]Department of Diabetes and Endocrinology, Luton and Dunstable Hospital NHS Foundation Trust, Luton, UK
                [6 ]İstanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Pediatric Endocrinology Unit, Istanbul, Turkey
                Author notes
                Correspondence and reprint requests: Professor Adrian J.L Clark, Centre for Endocrinology, First Floor North, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK, Tel; + 44-20-7882-6202, Fax; +44-20-7882-6197, a.j.clark@ 123456qmul.ac.uk
                Article
                UKMS48043
                10.1038/ng.2299
                3386896
                22634753
                87241f35-da27-4b8f-bd9d-8120d025f04c

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: Medical Research Council :
                Award ID: G0901980(93842) || MRC_
                Funded by: Medical Research Council :
                Award ID: G0801265(87957) || MRC_
                Funded by: Medical Research Council :
                Award ID: G0700767(82255) || MRC_
                Categories
                Article

                Genetics
                adrenal insufficiency,oxidative stress,reactive oxygen species,familial glucocorticoid deficiency

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