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Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
The incidence of congenital adrenal hypoplasia has been reported as 1 in 12,500 births. Inheritance is either as an autosomal or X-linked recessive condition. Mutations in the DAX1 gene are associated with the X-linked form of the disease. Autoimmune adrenal insufficiency is associated with the two types of polyglandular autoimmune syndrome (Table 13.2). Type I is associated with mutations in the AIRE (autoimmune regulator) gene on chromosome 21. Familial glucocorticoid deficiency (FGD) and triple A syndrome are characterised by an insensitivity to adrenocorticotrophic hormone (ACTH) concentrations. FGD is caused by mutations in the ACTH receptor (MC2R), or mutations in the MC2R accessory protein MRAP. More recently, mutations in the genes encoding nicotinamide nucleotide transhydrogenase (NNT) and minichromosome maintenance-deficient 4 (MCM4) have also been associated with FGD. Triple A syndrome is autosomal dominant and secondary to mutations in the ALADIN gene.
Sex Chromosome Anomalies
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
L. Hamerton John, A. Evans Jane
SRY is a transcription factor whose function is to initiate testicular differentiation in mammalian embryogenesis. The protein contains a high mobility group box (HMG), a DNA binding motif conserved among a broad class of nuclear proteins. Almost all of the published mutations associated with sex reversal in 46,XY females are located in the HMG box and affect the structure of the DNA binding domain (146). Other loci involved in XY sex reversal include SOX9 at 17q24, a transcription factor whose duplication leads to XX sex reversal, while mutations lead to XY gonadal dysgenesis and campomelic dysplasia. Mutations in SF1 at 9q33 result in adrenal insufficiency and XY gonadal dysgenesis. Mutations in DMRT1 at 9p24 result in XY gonadal dysgenesis. Mutations at the DAX1 locus, an antitestis gene at Xp21.3, result in congenital adrenal hypoplasia, while duplications of a 160 kb region result in XY gonadal dysgenesis (158). Clearly, extensive genetic heterogeneity exists in both XX and XY sex reversal. The process of sex determination is clearly highly complex and only partially understood (153,158-160).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The regulation of the CYP17A1 gene is complex. Induction of CYP17A1 has been found to be cAMP mediated and testosterone can suppress the induction of the enzyme. It has been shown that the regulation of homeodomain protein Pbx1 and protein kinase A interaction at −250/−241 is cAMP dependent. The 5′-flanking region of the CYP17A1 gene contains three functional SF1 elements that collectively mediate 25-fold or greater induction of promoter activity by SF1 (Hanley et al. 2001). In constructs containing all three functional SF1 elements, DAX1 inhibited this activation by at least 55%. In the presence of only one or two SF1 elements, DAX1 inhibition was lost although SF1 transactivation persisted.
Molecular cloning, characterization of dax1 gene and its response to progesterone in Misgurnus anguillicaudatus
Published in Drug and Chemical Toxicology, 2019
Weiran Huo, Ruyan Wan, Peijin Wang, Linxia Zhang, Xiaohua Xia
In conclusion, we have cloned the full-length cDNA of dax1 and characterized the spatio-temporal expression patterns of this gene. Ma-dax1 gene is highly conserved during vertebrate evolution and is involved in a wide range of developmental processes including embryogenesis, central nervous system development and gonad development. We found that, P4 could cause a disruption of sexual development and sex differentiation at environmentally relevant concentrations based on its regulation on dax1. The present findings will be helpful for similar studies aimed at further understanding of molecular mechanisms of the physiologic process of reproduction in fish. Further studies will be carried out to continue elucidating the precise role and mechanism of P4 in fish, especially in regards to complex regulatory mechanisms associated with the HPG axis.
Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Published in Systems Biology in Reproductive Medicine, 2019
MR Nagaraja, Satya Prakash Gubbala, C. R. Wilma Delphine Silvia, Ramars Amanchy
AR and SRD5A2 mutations were the commonly reported amongst cases of 46,XY DSD from Indian clinics. Mutations in AR, SRD5A2, MAMLD1, WT1, and MAP3K1 often presented hypospadias as one of the or as a soul dysmorphic feature. Deficits in testis-promoting, differentiation, and/or maintenance genes (such as SRY, WT1, DHH, NR5A1, and DMRT1) led to distinct dysmorphic phenotypes causing GD. SRY mutations were reported in patients diagnosed with gonadoblastoma, infertility, and hypogonadism. STAR and DAX1 mutations led to congenital lipoid adrenal hyperplasia and adrenal hypoplasia, respectively. In addition, a rare case of 46,XX DSD harbored CYP19A1 missense mutation that led to aromatase deficiency was reported.