Review Article| Volume 1, ISSUE 1, P13-22, 1988

Molecular biology of steroid hydroxylase deficiency

  • Peter J. Homsby
    Address reprint requests to: Peter J. Hornsby, Ph.D., Department of Cell and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
    Department of Cell and Molecular Biology, Medical College of Georgia, Augusta, Georgia
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      Recent advances in the molecular and cell biology of the steroid hydroxylase genes have begun to provide an explanation for the molecular basis of the steroid hydroxylase deficiencies. 21-Hydroxylase deficiency is one of the most frequent genetic diseases. Sequence data for the human 21-hydroxylase gene show that duplication of the 21-hydroxylase gene with creation of a pseudogene has occurred. Frequent recombination between the two genes may provide an “engine” for the continual generation of new mutant forms. 21-hydroxylase deficiency may result from deletions, alterations of primary sequence resulting in no protein product or a protein with altered properties, or alterations in upstream regulatory elements. A specific hypothesis considered here is that changes in the coding region of the gene may produce a protein with an unusually short half-life due to greater sensitivity to nonproductive cycling in the presence of steroid pseudosubstrates. Pseudosubstrate effects that have been studied in cultured adrenocortical cells are reviewed. Altered regulatory regions of the 21-hydroxylase gene could also selectively affect the enzyme in one region of the cortex if there were a mutation in a cyclic AMP-responsive sequence without an alteration in a putative C-kinase responsive sequence.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Pediatric and Adolescent Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • New MI
        Clinical and endocrinological aspects of 21-hydroxylase deficiency.
        Ann NY Acad Sci. 1985; 458: 1
        • New MI
        Congenital enzymatic defects of the adrenal.
        in: Anderson DC Winter JSD Adrenal Cortex. Butterworths, London1985: 153
        • White PC
        • Chaplin DD
        • Weis JH
        • et al.
        Two steroid 21-hydroxylase genes are located in the murine S region.
        Nature. 1984; 312: 465
        • Garlepp MJ
        • Wilton AN
        • Dawkins RL
        • et al.
        Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes.
        Immunogenetics. 1986; 23: 100
        • Stoner E
        • Dimartino-Nardi J
        • Kuhnle U
        • et al.
        Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect?.
        Clin Endocrinol. 1986; 24: 9
        • Donohoue PA
        • Van-Dop C
        • Jospe N
        • et al.
        Congenital adrenal hyperplasia. Molecular mechanisms resulting in 21-hydroxylase deficiency.
        Acta Endocrinol Suppl. 1986; 279: 315
        • Speiser PW
        • Dupont B
        • Rubinstein P
        • et al.
        High frequency of nonclassical steroid 21-hydroxylase deficiency.
        Am J Human Genet. 1985; 37: 650
        • Speiser PW
        • New MI
        Genotype and hormonal phe-notype in nonclassical 21-hydroxylase deficiency.
        J Clin Endocrinol Metab. 1987; 64: 86
        • Knorr D
        • Bidlingmaier F
        • Holler W
        • et al.
        Is heterozygosity for the steroid 21-hydroxylase deficiency responsible for hirsutism, premature pubarche, early puberty, and precocious puberty in children?.
        Acta Endocrinol Suppl. 1986; 279: 284
        • Child DF
        • Bu'lock DE
        • Anderson DC
        Adrenal steroidogenesis in hirsute women.
        Clin Endocrinol. 1980; 12: 595
        • Chrousos GP
        • Loriaux DL
        • Mann DL
        • et al.
        Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease.
        Ann Intern Med. 1982; 96: 143
        • Bongiovanni AM
        The response of several adrenocortical steroids to the administration of ACTH in hirsute women.
        J Steroid Biochem. 1983; 18: 745
        • Conway DI
        • Anderson DC
        • Gordon MT
        • et al.
        Adrenal progesterone, 17α-hydroxyprogesterone and Cortisol responses to synacthen in normal women and women with various gynaecological disorders.
        Clin Endocrinol. 1983; 19: 77
        • Dewailly D
        • Vantyghem-Haudiquet MC
        • Sainsard C
        • et al.
        Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency.
        J Clin Endocrinol Metab. 1986; 63: 418
        • Temeck JW
        • Pang SY
        • Nelson C
        • et al.
        Genetic defects of steroidogenesis in premature pubarche.
        J Clin Endocrinol Metab. 1987; 64: 609
        • Higashi Y
        • Yoshioka H
        • Yamane M
        • et al.
        Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome. A pseudo-gene and a genuine gene.
        Proc Natl Acad Sci USA. 1986; 83: 2841
        • White PC
        • New MI
        • Dupont B
        Structure of human steroid 21-hydroxylase genes.
        Proc Natl Acad Sci USA. 1986; 83: 5111
        • Phillips IR
        • Shephard EA
        Complementary genes for an adrenal enzyme deficiency.
        Nature. 1985; 314: 130
        • Chung BC
        • Matteson KJ
        • Miller WL
        Structure of a bovine gene for P-450c21 (steroid 21-hydroxylase) defines a novel cytochrome P-450 gene family.
        Proc Natl Acad Sci USA. 1986; 83: 4243
        • Chaplin DD
        • Galbraith LJ
        • Seidman JG
        • et al.
        Nucleotide sequence analysis of murine 21-hydroxylase genes. Mutations affecting gene expression.
        Proc Natl Acad Sci USA. 1986; 83: 9601
        • Parker KL
        • Chaplin DD
        • Wong M
        • et al.
        Expression of murine 21-hydroxylase in mouse adrenal glands and in transfected Yl adrenocortical tumor cells.
        Proc Natl Acad Sci USA. 1985; 82: 7860
        • White PC
        • New MI
        • Dupont B
        HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for 21-hydroxyla-tion.
        Proc Natl Acad Sci USA. 1984; 81: 7505
        • Werkmeister JW
        • New MI
        • Dupont B
        • et al.
        Frequent deletion and duplication of the steroid 21-hydroxylase genes.
        Am J Human Genet. 1986; 39: 461
        • Donohoue PA
        • van-Dop C
        • McLean RH
        • et al.
        Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein.
        J Clin Endocrinol Metab. 1986; 62: 995
        • Jospe N
        • Donohoue PA
        • van-Dop C
        • et al.
        Prevalence of polymorphic 21-hydroxylase gene (CA21HB) mutations in salt-losing congenital adrenal hyperplasia.
        Biochem Biophys Res Commun. 1987; 142: 798
        • Amor M
        • New MI
        • White PC
        A single base change in the OH21B gene causing steroid 21-hydroxylase deficiency.
        Endocrinology Suppl. 1987; 120: 272
        • Sharp PA
        Splicing of messenger RNA precursors.
        Science. 1987; 235: 766
        • Hornsby PJ
        Regulation of 21-hydroxylase activity by steroids in cultured bovine adrenocortical cells. Possible significance for adrenocortical androgen synthesis.
        Endocrinology. 1982; 111: 1092
        • Hornsby PJ
        • Crivello JF
        The role of lipid peroxidation and biological antioxidants in the function of the adrenal cortex. Part 1. A background review.
        Mol Cell Endocrinol. 1983; 30: 1
        • Hornsby PJ
        • Crivello JF
        The role of lipid peroxidation and biological antioxidants in the function of the adrenal cortex. Part 2.
        Mol Cell Endocrinol. 1983; 30: 123
        • Hornsby PJ
        Cytochrome P-450/pseudosubstrate interactions and the role of antioxidants in the adrenal cortex.
        Endocrine Res. 1986; 12: 469
        • Hornsby PJ
        Cytochrome P-450/pseudosubstrate interactions in the adrenal cortex and their possible role in adrenocortical pathology.
        in: Mantero F. Vecsei P. Corticosteroids and Peptide Hormones in Hypertension. Raven Press, New York1987: 11-25
      1. Hornsby PJ: Physiological and pathological effects of steroids on the function of the adrenal cortex. J Steroid Biochem (in press)

        • Narasimhulu S
        Uncoupling of oxygen activation from hydroxylation in the steroid C-21 hydroxylase of bovine adrenocortical microsomes.
        Arch Biochem Biophys. 1971; 147: 384
        • Schenkman JB
        • Sligar SG
        • Cinti DL
        Substrate interaction with cytochrome P-450.
        Pharmacol Ther. 1981; 12: 43
        • Neville AM
        • O'Hare MJ
        The Human Adrenal Cortex. Pathology and Biology—An Integrated Approach. Springer-Verlag, Berlin1982
        • Hornsby PJ
        • Aldern KA
        • Harris SE
        Methylcholan-threne. A possible pseudosubstrate for adrenocortical 17a-hydroxylase and aryl hydrocarbon hydroxylase.
        Biochem Pharmacol. 1986; 35: 3209
        • Crivello JF
        • Hornsby PJ
        • Gill GN
        Metyrapone and an-tioxidants are required to maintain aldosterone synthesis by cultured bovine adrenocortical cells.
        Endocrinology. 1982; 111: 469
        • Crivello JF
        • Gill GN
        Induction of cultured bovine adrenocortical zona glomerulosa cell 17-hydroxylase activity by ACTH.
        Mol Cell Endocrinol. 1983; 30: 97
        • Boehm BO
        • Rosak C
        • Kuehnl P
        • et al.
        Late-onset form of congenital adrenal hyperplasia in the HLA-B14; DR1 haplotype is caused by a duplication in the 21-OH MHC gene region.
        Horm Metab Res. 1986; 18: 791
        • Mornet E
        • Couillin P
        • Kutten F
        • et al.
        Associations between restriction fragment length polymorphisms detected with a probe for human 21-hydroxylase (21-OH) and two clinical forms of 21-OH deficiency.
        Human Genet. 1986; 74: 402
        • Waterman MR
        • Simpson ER
        Regulation of the biosynthesis of cytochromes P-450 involved in steroid hormone synthesis.
        Mol Cell Endocrinol. 1985; 39: 81
        • Hornsby PJ
        • Aldern KA
        Steroidogenic enzyme activities in cultured human definitive zone adrenocortical cells. Comparison with bovine adrenocortical cells and resultant differences in adrenal androgen synthesis.
        J Clin Endocrinol Metab. 1984; 58: 121
        • Purvis JL
        • Canick JA
        • Mason JI
        • et al.
        Lifetime of adrenal cytochrome P-450 as influenced by ACTH.
        Ann NY Acad Sci. 1973; 212: 319
        • Funkenstein B
        • McCarthy JL
        • Dus KM
        • et al.
        Effect of adrenocorticotropin on steroid 21-hydroxylase synthesis and activity in cultured bovine adrenocortical cells. Increased synthesis in the absence of increased activity.
        J Biol Chem. 1983; 258: 9398
        • John ME
        • Okamura T
        • Dee A
        • et al.
        Bovine steroid 21-hydroxylase. Regulation of biosynthesis.
        Biochemistry. 1986; 25: 2846
        • John ME
        • John MC
        • Boggaram V
        • et al.
        Transcriptional regulation of steroid hydroxylase genes by corticotropin.
        Proc Natl Acad Sci USA. 1986; 83: 4715
        • Parker KL
        • Chaplin DD
        • Wong M
        • et al.
        Molecular analysis of 21-hydroxylase gene expression in mouse adrenal cells.
        Endocrine Res. 1986; 12: 409
        • Parker KL
        • Schimmer BP
        • Chaplin DD
        • et al.
        Characterization of a regulatory region of the steroid 21-hydroxylase gene.
        J Biol Chem. 1986; 261: 15353
        • Nagamine Y
        • Reich E
        Gene expression and cAMP.
        Proc Natl Acad Sci USA. 1985; 82: 4606
        • Wynshaw-Boris A
        • Short JM
        • Hanson RW
        The determination of sequence requirements for hormonal regulation of gene expression.
        BioTechniques. 1986; 4: 104
        • Rasmussen H
        • Kojima I
        • Kojima K
        • et al.
        Calcium as intracellular messenger. Sensitivity modulation, C-kinase pathway, and sustained cellular response.
        Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984; 18: 59
        • McAllister JM
        • Hornsby PJ
        TPA inhibits the synthesis of androgens and Cortisol and enhances the synthesis of non-17α-hydroxylated steroids in cultured human adrenocortical cells.
        Endocrinology. 1987; 121: 1908
        • McAllister JM
        • Hornsby PJ
        Dual regulation of 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and DHEA sulfotransferase by cyclic AMP and activators of protein kinase C in cultured human adrenocortical cells.
        Endocrinology. 1988; (in press)
      2. Hornsby PJ: The mechanism of action of ACTH on the adrenal cortex. New Comprehensive Biochemistry. Edited by BA Cooke, RJB King, HJ van der Molen. Amsterdam, Elsevier (in press)

        • Angel P
        • Rahmsdorf HJ
        • Pöting A
        • et al.
        12-O-Tetra-decanoylphorbol-13-acetate (TPA)-induced gene sequences in human primary diploid fibroblasts and their expression in SV40-transformed fibroblasts.
        J Cell Biochem. 1985; 29: 351
        • Rabin MS
        • Doherty PJ
        • Gottesman MM
        The tumor promoter phorbol 12-myristate 13-acetate induces a program of altered gene expression similar to that induced by platelet-derived growth factor and transforming oncogenes.
        Proc Natl Acad Sci USA. 1986; 83: 357
        • Elsholtz HP
        • Mangalam HJ
        • Potter E
        • et al.
        Two different cis-active elements transfer the transcriptional effects of both EGF and phorbol esters.
        Science. 1986; 234: 1552