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 language | English (US) |
|---|---|
| Pages (from-to) | 70-78 |
| Number of pages | 9 |
| Journal | BBA Clinical |
| Volume | 3 |
| DOIs | |
| State | Published - Jun 1 2015 |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=84920173685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920173685&partnerID=8YFLogxK
U2 - 10.1016/j.bbacli.2014.12.003
DO - 10.1016/j.bbacli.2014.12.003
M3 - Article
AN - SCOPUS:84920173685
VL - 3
SP - 70
EP - 78
JO - BBA Clinical
JF - BBA Clinical
SN - 2214-6474
ER -