AHC manifests itself mainly in early infancy or in childhood and is caused by deletions or point mutations in the NR0B1 (DAX1) (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene (OMIM*300473) (Figures 1(a)-1(c)) .
NR0B1 (DAX1) is a transcriptional repressor of other proteins involved in the adrenal steroidogenesis pathway such as steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), P450scc, and 3[beta]-hydroxysteroid dehydrogenase [7, 8].
Almost two hundred mutations in the NR0B1 (DAX1) gene have been identified to date , and the relationship between mutations in the NR0B1 (DAX1) gene and AHC is well documented.
Other pathogenic alterations that affect the NR0B1 (DAX1) gene comprise copy-number variations (CNVs) of different size.
NR0B1 (DAX1) is crucial for the development of the adrenal glands and the hypothalamic-pituitary-gonadal axis; hence its disruption can result in various clinical phenotypes leading to Adrenal Hypoplasia Congenita (AHC).
Hypogonadotropic hypogonadism (HH) is the most frequently observed puberty disorder that is caused by mutations in the NR0B1 (DAX1) gene and is due to impaired gonadotropin synthesis and release.
Genes frequently involved in complex GKD include DMD, variations in which cause Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), and NR0B1 (DAX1), which is responsible for adrenal hypoplasia congenita (AHC) (2, 3).
The orientation of the included genes is: Xpter-IL1RAPL1 (5' [right arrow] 3') NR0B1 (3' [left arrow] 5') GK (5' [right arrow] 3') DMD (3' [leaf arrow] 5')-cent.
Primers were designed to flank the termination codon of the IL1RAPL1 coding sequence and junction, the start codon of the NR0B1 gene and junction, the GK promoter region, and the termination codon within DMD exon 79 and the accompanying 3' junction with the untranslated region (Table 1, Fig.
Complex GKD is a rare disorder but one that is important to recognize because of the potential for life-threatening Addisonian crises in patients whose deletions extend into the NR0B1 gene.
The PCR assay that we designed maps the gene deletion to the 4 loci most commonly associated with complex GKD (IL1RAPL1, NR0B1, GK, and DMD).
4] Human genes: NR0B1 (DAX1), nuclear receptor subfamily 0, group B, member 1; DMD, dystrophin (muscular dystrophy, Duchenne and Becker types); IL1RAPL1, interleukin 1 receptor accessory protein-like 1; GK, glycerol kinase; OTC, ornithine carbamoyl transferase.