Affiliation:
1. Department of Pediatrics, Medical University of Lübeck, Lübeck, Germany D-23538
Abstract
In a patient with partial androgen insensitivity syndrome (AIS), we identified a single inherited presumably silent nucleotide variation (AGC -> AGT) in exon 8 (codon 888) of the AR gene. However, in the patient’s genital skin fibroblasts, a considerably shortened transcript of 5.5 kb (normal: 10.5 kb) was detected, which misses a part of exon 8 and a prominent portion of the 3′-untranslated region. The translation product includes eight missense amino acids from codon 886 onward followed by a premature stop codon. As shown by in vitro expression analysis, the mutant protein lacks any residual function. However, reverse transcribed PCRs and sequence data indicate the existence of two additional splicing variants of 6.4 kb and 7.8-kb length both in patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3′-untranslated region. Thus, a distinct alternative pre-messegner RNA-processing event leading to two additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functionally intact AR-protein that could explain the partial masculinization in this patient.
This first report of an exonic splicing mutation in the AR-gene indicates a physiologic relevance of the regular AR-messenger RNA variants with shortened 3′-untranslated regions and their functional translation products in human genital development.
Subject
Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism
Reference28 articles.
1. Transcriptional regulation by steroid hormones;Beato;Steroids,1996
2. Transcriptional activation and nuclear targeting signals of the human androgen receptor;Simental;J Biol Chem.,1991
3. Androgen receptor defects;Quigley;Historical, clinical and molecular perspectives. Endocr Rev.,1995
4. Cloning of human androgen receptor complementary DNA and localization to the X chromosome;Lubahn;Science,1988
5. Molecular cloning of human and rat complementary DNA encoding androgen receptors;Chang;Science,1988
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献