title: Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency.
abstract: BACKGROUND
  Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations.
  
  
  METHODS
  Clinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutation.
  
  
  RESULTS
  In this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644T>C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of controls.
  
  
  CONCLUSIONS
  Our results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6J (NNT-/-) vs. C57BL/6JN (NNT+/+) substrains.
  
  
  CONCLUSIONS
  By studying a family affected with a novel point mutation in the NNT gene, a gene-dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress.
authors: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors: Yasuko
authors: Y
authors: Fujisawa
authors: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA.
authors: Eleonora
authors: E
authors: Napoli
authors: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA.
authors: Sarah
authors: S
authors: Wong
authors: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA.
authors: Gyu
authors: G
authors: Song
authors: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors: Rie
authors: R
authors: Yamaguchi
authors: Department of Pediatrics, Nagaoka Chuo General Hospital, Nagaoka 940-8653, Japan.
authors: Toshiharu
authors: T
authors: Matsui
authors: Division of Pediatrics, Niigata University Graduate School of Medicine and Dental Sciences, Niigata 951-8122, Japan.
authors: Keisuke
authors: K
authors: Nagasaki
authors: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors: Tsutomu
authors: T
authors: Ogata
authors: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA ; Medical Investigations of Neurodevelopmental Disorders (M. I. N. D.) Institute, University of California Davis, Sacramento, CA 95616.
authors: Cecilia
authors: C
authors: Giulivi
keywords: Familial glucocorticoid deficiency; mitochondrial biogenesis; mitochondrial replication; nicotinamide nucleotide transhydrogenase; oxidative phosphorylation; oxidative stress