Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency Article First Online: 25 January 2007 Received: 27 June 2006 Accepted: 16 December 2006 DOI:
Cite this article as: Buss, C., Schuelter, U., Hesse, J. et al. J Neural Transm (2007) 114: 563. doi:10.1007/s00702-006-0620-5 Summary.
Corticosteroid-binding globulin (SERPINA6) deficiency is an extremely rare hereditary disorder characterized by reduced corticosteroid-binding capacity with normal or low plasma corticosteroid-binding globulin concentration, and normal or low basal cortisol levels associated with hypo-/hypertension and muscle fatigue. Here, we present a patient with severe muscle fatigue, normal blood pressure, and abnormal high saliva cortisol levels following a standardized stress test. This patient was found heterozygous for a
de novo 367 asparagine-encoding variant of the corticosteroid-binding globulin gene, previously described as “transcortin Lyon”. Both parents were homozygous for the (“wildtype”) 367 aspartate-encoding allele. To the best of our knowledge, this case represents the first de novo mutation reported for corticosteroid-binding globulin deficiency, implicating a pathogenic role of variants of SERPINA6 in some cases of muscle fatigue. Keywords: Corticosteroid-binding globulin deficiency, SERPINA6, mutation analysis References Bank, WJ, DiMauro, S, Bonilla, E, Capuzzi, DM, Rowland, LP 1975 A disorder of muscle lipid metabolism and myoglobinuria. Absence of carnitine palmityl transferase N Engl J Med 292 443 449 PubMed CrossRef Google Scholar Brais, B, Bouchard, JP, Xie, YG, Rochefort, DL, Chretien, N, Tome, FM, Lafreniere, RG, Rommens, JM, Uyama, E, Nohira, O, et al. 1998 Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy Nat Genet 18 164 167 PubMed CrossRef Google Scholar Brunner, E, Baima, J, Vieira, TC, Vieira, JG, Abucham, J 2003 Hereditary corticosteroid-binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred Clin Endocrinol (Oxf) 58 756 762 CrossRef Google Scholar Dhillo, WS, Kong, WM, Le Roux, CW, Alaghband-Zadeh, J, Jones, J, Carter, G, Mendoza, N, Meeran, K, O’Shea, D 2002 Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic – pituitary – adrenal axis Eur J Endocrinol 146 231 235 PubMed CrossRef Google Scholar Doe, RP, Lohrenz, FN, Seal, US 1965 Familial decrease in corticosteroid-binding globulin Metabolism 14 940 943 PubMed CrossRef Google Scholar Dressendorfer, RA, Kirschbaum, C, Rohde, W, Stahl, F, Strasburger, CJ 1992 Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement J Steroid Biochem Mol Biol 43 683 692 PubMed CrossRef Google Scholar Emptoz-Bonneton, A, Cousin, P, Seguchi, K, Avvakumov, GV, Bully, C, Hammond, GL, Pugeat, M 2000 Novel human corticosteroid-binding globulin variant with low cortisol-binding affinity J Clin Endocrinol Metab 85 361 367 PubMed CrossRef Google Scholar Hellhammer, J, Schlotz, W, Stone, AA, Pirke, KM, Hellhammer, D 2004 Allostatic load, perceived stress, and health: a prospective study in two age groups Ann NY Acad Sci 1032 8 13 PubMed CrossRef Google Scholar Kirschbaum, C, Hellhammer, DH 1994 Salivary cortisol in psychoneuroendocrine research: recent developments and applications Psychoneuroendocrinology 19 313 333 PubMed CrossRef Google Scholar Kirschbaum, C, Pirke, KM, Hellhammer, DH 1993 The ‘Trier Social Stress Test’ – a tool for investigating psychobiological stress responses in a laboratory setting Neuropsychobiology 28 76 81 PubMed CrossRef Google Scholar Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, Devon, K, Dewar, K, Doyle, M, FitzHugh, W, et al. 2001 Initial sequencing and analysis of the human genome Nature 409 860 921 PubMed CrossRef Google Scholar Meaney, MJ, Diorio, J, Francis, D, Widdowson, J, LaPlante, P, Caldji, C, Sharma, S, Seckl, JR, Plotsky, PM 1996 Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress Dev Neurosci 18 49 72 PubMed Google Scholar Reynolds, RM, Walker, BR, Syddall, HE, Andrew, R, Wood, PJ, Whorwood, CB, Phillips, DI 2001 Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors J Clin Endocrinol Metab 86 245 250 PubMed CrossRef Google Scholar Smedes, F, Kraak, JC, Poppe, H 1982 Simple and fast solvent extraction system for selective and quantitative isolation of adrenaline, noradrenaline and dopamine from plasma and urine J Chromatogr 231 25 39 PubMed CrossRef Google Scholar Torpy, DJ, Bachmann, AW, Grice, JE, Fitzgerald, SP, Phillips, PJ, Whitworth, JA, Jackson, RV 2001 Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension J Clin Endocrinol Metab 86 3692 3700 PubMed CrossRef Google Scholar Van Baelen, H, Brepoels, R, De Moor, P 1982 Transcortin Leuven: a variant of human corticosteroid-binding globulin with decreased cortisol-binding affinity J Biol Chem 257 3397 3400 PubMed Google Scholar Van Baelen, H, Power, SG, Hammond, GL 1993 Decreased cortisol-binding affinity of transcortin Leuven is associated with an amino acid substitution at residue-93 Steroids 58 275 277 PubMed CrossRef Google Scholar Vining, RF, McGinley, RA 1987 The measurement of hormones in saliva: possibilities and pitfalls J Steroid Biochem 27 81 94 PubMed CrossRef Google Scholar Zubieta, JK, Heitzeg, MM, Smith, YR, Bueller, JA, Xu, K, Xu, Y, Koeppe, RA, Stohler, CS, Goldman, D 2003 COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor Science 299 1240 1243 PubMed CrossRef Google Scholar