A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by primary hypocortisolism and normal mineralocorticoid production. Recently, NNT encoding the nicotinamide nucleotide transhydrogenase has been identified as a causative gene for FGD. Thus, we examined NNT...

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Bibliographic Details
Published in:Endocrine Journal 2013, Vol.60(7), pp.855-859
Main Authors: Yamaguchi, Rie, Kato, Fumiko, Hasegawa, Tomonobu, Katsumata, Noriyuki, Fukami, Maki, Matsui, Toshiharu, Nagasaki, Keisuke, Ogata, Tsutomu
Format: Article
Language:English
Subjects:
Adolescent
Adrenal Insufficiency - genetics
Asian Continental Ancestry Group
DNA Mutational Analysis
Familial glucocorticoid deficiency
Glucocorticoids - deficiency
Homozygote
Humans
In silico functional analysis
Male
Mutation, Missense - physiology
NADP Transhydrogenases - genetics
NNT
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Summary:Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by primary hypocortisolism and normal mineralocorticoid production. Recently, NNT encoding the nicotinamide nucleotide transhydrogenase has been identified as a causative gene for FGD. Thus, we examined NNT in six Japanese FGD patients with no recognizable mutation in the previously known four responsible genes for FGD (MC2R, MRAP, STAR, and MCM4), and identified a novel homozygous substitution (c.644T>C; p.Phe215Ser) in a single 17.5-year-old boy. His parents were heterozygous for this mutation. This substitution was absent from 120 Japanese control subjects and was not registered in public databases including JSNP Database. The phenylalanine residue at the 215th codon was evolutionally conserved, and the p.Phe215Ser was assessed to be a pathologic mutation by in silico protein function analyses. The results, in conjunction with the previous data, imply that NNT mutations account for 5-10% of FGD patients, and that underlying factor(s) still remains to be clarified in a substantial fraction of FGD patients.
ISSN:0918-8959
1348-4540
DOI:10.1507/endocrj.EJ13-0024