Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

Yasuko Fujisawa, Eleonora Napoli, Sarah Wong, Gyu Song, Rie Yamaguchi, Toshiharu Matsui, Keisuke Nagasaki, Tsutomu Ogata, Cecilia R Giulivi

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 were performed. 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 the 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. General significance: 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.

Original languageEnglish (US)
Pages (from-to)70-78
Number of pages9
JournalBBA Clinical
Volume3
DOIs
StatePublished - Jun 1 2015

Fingerprint

NADP Transhydrogenases
Mitochondrial DNA
Glucocorticoids
Mutation
Mitochondria
Genes
Citrate (si)-Synthase
Mitochondrial Genes
Organelle Biogenesis

Keywords

  • Familial glucocorticoid deficiency
  • Mitochondrial biogenesis
  • Mitochondrial replication
  • Nicotinamide nucleotide transhydrogenase
  • Oxidative phosphorylation
  • Oxidative stress

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology (medical)
  • Molecular Medicine

Cite this

Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. / Fujisawa, Yasuko; Napoli, Eleonora; Wong, Sarah; Song, Gyu; Yamaguchi, Rie; Matsui, Toshiharu; Nagasaki, Keisuke; Ogata, Tsutomu; Giulivi, Cecilia R.

In: BBA Clinical, Vol. 3, 01.06.2015, p. 70-78.

Research output: Contribution to journalArticle

Fujisawa, Yasuko ; Napoli, Eleonora ; Wong, Sarah ; Song, Gyu ; Yamaguchi, Rie ; Matsui, Toshiharu ; Nagasaki, Keisuke ; Ogata, Tsutomu ; Giulivi, Cecilia R. / Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. In: BBA Clinical. 2015 ; Vol. 3. pp. 70-78.
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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 were performed. 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 the 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. General significance: 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.",
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T1 - Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

AU - Fujisawa, Yasuko

AU - Napoli, Eleonora

AU - Wong, Sarah

AU - Song, Gyu

AU - Yamaguchi, Rie

AU - Matsui, Toshiharu

AU - Nagasaki, Keisuke

AU - Ogata, Tsutomu

AU - Giulivi, Cecilia R

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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 were performed. 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 the 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. General significance: 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.

AB - 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 were performed. 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 the 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. General significance: 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.

KW - Familial glucocorticoid deficiency

KW - Mitochondrial biogenesis

KW - Mitochondrial replication

KW - Nicotinamide nucleotide transhydrogenase

KW - Oxidative phosphorylation

KW - Oxidative stress

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