NR0B1 (DAX1) mutations in patients affected by congenital adrenal hypoplasia with growth hormone deficiency as a new finding

Abstract

X-linked adrenal hypoplasia congenita (AHC,OMIM#300200) is a rare disorder of the adrenal cortex caused bymutations in the NR0B1 (DAX1) (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene (OMIM*300473). NR0B1 (DAX1) is located on the short arm of the X chromosome (Xp21.3-p21.2) and encodes for an orphan nuclear hormone receptor (transcription factor) (Zanaria et al. 1994). NR0B1 (DAX1) is expressed in the adrenals, gonads, hypothalamus, and pituitary gland, and it is responsible for controlling the development and function of these tissues. NR0B1 (DAX1) protein functions as a dominant negative regulator (transcriptional repressor) in the hypothalamic– pituitary–adrenal–gonadal axis. It regulates the expression of other proteins involved in the adrenal steroidogenesis pathway, such as steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), P450scc and 3β-hydroxysteroid dehydrogenase (Lalli et al. 2000; Iyer and McCabe 2004). Almost 200 mutations in theNR0B1 (DAX1) gene have been identified to date (The Human Gene Mutation Database—data for 10.08.11) (http://www.hgmd.org). The most commonly found mutations in AHC patients are frameshift and nonsense mutations, which are located throughout the entire length of the NR0B1 (DAX1) gene. Missense mutations are not so common and are located mainly in the region that encodes for a ligandbinding domain at the C-terminus of the NR0B1 (DAX1) protein (Achermann et al. 2001a). Some patients have more complex X-chromosome rearrangements that include the deletion of larger parts of the X chromosome, including NR0B1 (DAX1), DMD (dystrophin), GK (glycerol kinase) and IL1RAPL (interleukin 1 receptor accessory protein-like) genes (Choi et al. 2005). AHC symptoms are noticed very early in postnatal life. The disorder is characterized by salt-wasting syndrome, hypoglycemia in early infancy or childhood, poor weight gain, vomiting, prolonged neonatal jaundice, and skin hyperpigmentation. In laboratory tests, hyponatremia, hyperkalemia, low levels of cortisol, aldosterone, and adrenal androgens are found, in contrast to high levels of adrenocorticotropic hormone (ACTH) and plasma renin activity (Achermann et al. 2000; Nakae et al. 1997; Wiltshire et al. 2001; Verrijn Stuart et al. 2007). Very frequently, patients are admitted to hospital in a life-threatening condition. AHC is lethal unless appropriate steroid replacement therapy is provided to these patients. Most patients with AHC also suffer from hypogonadotropic hypogonadism, since mutations in the NR0B1 (DAX1) gene A. Rojek (*) :M. Niedziela 2nd Chair of Pediatrics, Department of Pediatric Endocrinology and Rheumatology, Molecular Endocrinology Laboratory, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznan, Poland e-mail: aleksandra.rojek@gmail.com