Aberrant splicing of androgenic receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity

Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symtpoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. The authors report a G {r arrow} T mutation in the spli...

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Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 87:20
Main Authors Ris-Stalpers, C., Kuiper, G.G.J.M., Faber, P.W., van Rooij, H.C.J., Degenhart, H.J., Trapman, J., Brinkmann, A.O., Schweikert, H.U., Zegers, N.D., Hodgins, M.B.
Format Journal Article
LanguageEnglish
Published United States 01.10.1990
Subjects
550201 - Biochemistry- Tracer Techniques
ANDROGENS
ANDROSTANES
BASIC BIOLOGICAL SCIENCES
BIOSYNTHESIS
DISEASES
DNA BASE TRANSITIONS
ESTROGENS
GENE AMPLIFICATION
GENE MUTATIONS
HEREDITARY DISEASES
HORMONES
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
MEMBRANE PROTEINS
MESSENGER-RNA
MUTATIONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PATIENTS
PROTEINS
RADIORECEPTOR ASSAY
RECEPTORS
RNA
STEROID HORMONES
STEROIDS
SYNTHESIS
TRACER TECHNIQUES
TRANSCRIPTION
TRITIUM COMPOUNDS
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Summary:Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symtpoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. The authors report a G {r arrow} T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46, XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein {approx}5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.87.20.7866