Abstract
BackgroundFamilial 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. MethodsClinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutation were performed. ResultsIn 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. ConclusionsOur 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 significanceBy 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.
Highlights
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency [1] reported for the first time in 1959 [2]
The non-energy linked activity of nicotinamide nucleotide transhydrogenase (NNT) was evaluated in mitochondria-enriched fractions from lymphocytes obtained from a 21 y old patient, his parents and controls
The NNT specific activity [defined as the activity expressed as nmol product ×−1 normalized by the NNT protein levels] in the patient's sample was 31% of the mean control value and 56% of his parents (Table 1), both values outside the 95%CI
Summary
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency [1] reported for the first time in 1959 [2]. The long-term neurological consequences of FGD can vary from learning difficulties, mild dementia [6], spastic quadriplegia [16,17], which may reflect the severity and number of hypoglycemic episodes during childhood [17]. This disease is treatable when recognized, hypoglycemic attacks and convulsions may result in coma or even death [18]. Results: In this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644TNC; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. 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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