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Cited by 50Sexual Differentiation and DisordersAdrenal Hormones and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Molecular basis of apparent isolated 17,20-lyase deficiency: compound heterozygous mutations in the C-terminal region (Arg(496) → Cys, Gln(461) → Stop) actually cause combined 17α-hydroxylase/17,20-lyase deficiency

Yanase, Toshihiko, Waterman, Michael R., Zachmann, Milo, Winter, J.S.D., Simpson, Evan R, Kagimoto, Masaaki·1992·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
DOI 10.1016/0925-4439(92)90100-2
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Abstract

The molecular defect in a reported case of isolated 17,20-lyase deficiency in a 46XY individual has been elucidated. The patient was found to be a compound heterozygote, carrying two different mutant alleles in the CYP17 gene. One allele contains a point mutation of arginine (CGC) to cysteine (TGC) at amino acid 496 in exon 8. The second allele contains a stop codon (TAG) in place of glutamine (CAG) at position 461 in exon 8 which is located 19 amino acids to the carboxy-terminal side of the P-450(17) alpha heme binding cysteine. COS-1 cells transfected with cDNAs containing one or the other of these mutations showed dramatically reduced 17 alpha-hydroxylase and 17,20-lyase activities relative to cells transfected with the wild type P-450(17) alpha cDNA. While the in vitro data in COS 1 cells can explain the patient's physical phenotype, with female external genitalia, it was somewhat discordant with the clinical expression of isolated 17,20-lyase deficiency with relative preservation of 17 alpha-hydroxylase activity in vivo. In addition to the expression studies of these two examples of mutants in the C-terminal region of cytochrome P-450(17) alpha, a third mutant cDNA construct containing a 4-base duplication at codon 480 previously found in patients with combined 17 alpha-hydroxylase/17,20-lyase deficiency was also expressed in COS-1 cells. This expressed protein was completely inactive with respect to both activities, supporting the biochemical findings in serum and in vitro biochemical data obtained using a testis from the patient. The results from these patients clearly indicate the importance of the C-terminal region of human P-450(17) alpha in its enzymatic activities.

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  • One original patient with apparent isolated 17,20-lyase deficiency was studied genetically and had two wholly inactivating mutations, leading to a corrected diagnosis of complete 17α-hydroxylase deficiency.

    “One of the original patients was studied at the genetic level, showing two wholly inactivating mutations (277), which led to a corrected diagnosis of the patient as having complete 17␣-hydroxylase deficiency (278).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [277]

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Authors
Yanase, T., Waterman, M. R., Zachmann, M., Winter, J. S. D., Simpson, E. R., & Kagimoto, M.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • University of Zurich (CH)
  • University of Alberta (CA)
Corresponding author
Waterman, Michael R.
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher
Elsevier BV
Published
1992-08
Volume
1139
Issue
4
Pages
275-279
ISSN
0925-4439 (ISSN-L)
DOI
10.1016/0925-4439(92)90100-2
OpenAlex
W2164097694
Cited by
50
References
5
Citations by year
2026: 1 · 2022: 1 · 2016: 1 · 2013: 1 · 2012: 1
FWCI
1.32
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • March of Dimes Foundation
  • U.S. Public Health Service
  • National Institute of General Medical Sciences (GM-37942)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
17,20-lyase deficiency, CYP17 gene, compound heterozygosity, C-terminal region, stop codon mutation, female external genitalia, enzyme activity
MeSH terms
Adolescent, Adrenal Hyperplasia, Congenital, Aldehyde-Lyases, Amino Acid Sequence, Base Sequence, Cell Line, Cytochrome P-450 Enzyme System, Heterozygote, Humans, Male, Molecular Sequence Data, Mutation, Disorders of Sex Development, Transfection

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