Abstract
Both salt-losing and non-salt-losing 21-hydroxylase deficiency have been associated with a deleterious conversion event at nucleotide 655 (A or C in CYP21) to the CYP21P sequence (G) which modifies mRNA splicing leading to an elongated translation product with altered enzyme activity (PNAS 1988; 85:7486). To determine if the DNA binding region for a cAMP-dependent adrenal specific nuclear TF (JBC 1991; 266:11199) could account for this phenotypic heterogeneity, we determined the sequence of this functionally conserved region (-134 to -122) in 3 patients (2 salt-losing: 1 non-salt-losing) with this mutation. An 849-bp region of CYP21 was amplified by PCR utilizing a biotinylated primer. Sequencing was performed (SequenaseR) following DynabeadR magnetic avidin-biotin separation. The presence of other reported mutations was assessed by hybridization of specific oligonucleotide probes.
Patient 1 (46,XY) presented at 3 weeks of age with glucocorticoid & mineralocorticoid deficiencies. Patient 2 (46,XX), assigned to a male sex of rearing at birth, presented at 4 years of age with premature virilization. Patient 3 (46,XX) presented at birth with ambiguous genitalia and elevated plasma renin activity. Patients 1 & 3 have G at position 655 on both CYP21 alleles while patient 2 inherited a deletion for this region from his mother & G from his father. No sequence alterations were detected in these 3 patients from -160 to -80 of the 5′ noncoding region of CYP21. Patients 1 & 2 have the normal CYP21 sequence forcodons 172, 236, 237, 239, 306. 318, and 356 (analysis is incomplete for patient 3).
Differences in regulation through TFs could be postulated as an etiology of phenotypic heterogeneity. However, in these 3 patients, the sequence where the adrenal specific binding protein interacts with DNA is conserved. The basis for the phenotypic heterogeneity may be due to as yet undefined alterations in the coding or promoter regions of CYP21.
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Siegel, S., Rudert, W., Lee, P. et al. ADRENAL SPECIFIC NUCLEAR TRANSCRIPTION FACTOR (TF) BINDING REGION IN 21-HYDROXYLASE DEFICIENCY. Pediatr Res 33 (Suppl 5), S18 (1993). https://doi.org/10.1203/00006450-199305001-00089
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DOI: https://doi.org/10.1203/00006450-199305001-00089