A recurrent germline mutation in the 5'UTR of the androgen receptor causes complete androgen insensitivity by activating aberrant uORF translation

PLoS ONE

Volumn 11, Issue 4, 2016, Pages

  Hornig, Nadine C ^a   De Beaufort, Carine ^b   Denzer, Friederike ^c   Cools, Martine ^d   Wabitsch, Martin ^c   Ukat, Martin ^a   Kulle, Alexandra E ^a   Schweikert, Hans Udo ^e   Werner, Ralf ^f   Hiort, Olaf ^f   Audi, Laura ^g   Siebert, Reiner ^a   Ammerpohl, Ole ^a   Holterhus, Paul Martin ^a  

^a UNIVERSITY OF KIEL   (Germany)

^b Pediatric clinic   (Luxembourg)

^c UNIVERSITY OF ULM   (Germany)

^d GHENT UNIVERSITY HOSPITAL   (Belgium)

^e UNIVERSITY OF BONN   (Germany)

^f UNIVERSITY OF LÜBECK   (Germany)

^g HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; AR PROTEIN, HUMAN; LUCIFERASE;

5' UNTRANSLATED REGION; ANDROGEN RECEPTOR GENE; ARTICLE; COMPLETE ANDROGEN INSENSITIVITY SYNDROME; CONTROLLED STUDY; DISEASE ACTIVITY; DISEASE ASSOCIATION; GENE; GENE EXPRESSION; GENE FUNCTION; GENE IDENTIFICATION; GERMLINE MUTATION; HUMAN; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; MALE; MOLECULAR DYNAMICS; MOLECULAR PATHOLOGY; OPEN READING FRAME; PROTEIN EXPRESSION; PROTEIN FUNCTION; TRANSLATION REGULATION; ANDROGEN INSENSITIVITY SYNDROME; DNA SEQUENCE; FIBROBLAST; FRAMESHIFT MUTATION; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NUCLEOTIDE SEQUENCE; PATHOLOGY; PRIMARY CELL CULTURE; PROTEIN SYNTHESIS; REPORTER GENE;

5' UNTRANSLATED REGIONS; ANDROGEN-INSENSITIVITY SYNDROME; BASE SEQUENCE; FIBROBLASTS; FRAMESHIFT MUTATION; GENE EXPRESSION REGULATION; GENES, REPORTER; GERM-LINE MUTATION; HUMANS; LUCIFERASES; MALE; OPEN READING FRAMES; PRIMARY CELL CULTURE; PROTEIN BIOSYNTHESIS; RECEPTORS, ANDROGEN; SEQUENCE ANALYSIS, DNA;

EID: 84964789129     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0154158     Document Type: Article

References (29)

1. de Moor CH, Meijer H, Lissenden S. Mechanisms of translational control by the 3' UTR in development and differentiation. Seminars in cell & developmental biology. 2005; 16(1):49-58. Epub 2005/01/22. oi: 10.1016/j.semcdb.2004.11.007 PMID: 15659339.
2. Araujo PR, Yoon K, Ko D, Smith AD, Qiao M, Suresh U, et al. Before It Gets Started: Regulating Translation at the 5' UTR. Comparative and functional genomics. 2012; 2012:475731. Epub 2012/06/14. doi: 10.1155/2012/475731 PMID: 22693426; PubMed Central PMCID: PMC3368165.
3. Barbosa C, Peixeiro I, Romao L. Gene expression regulation by upstream open reading frames and human disease. PLoS genetics. 2013; 9(8):e1003529. Epub 2013/08/21. doi: 10.1371/journal.pgen. 003529 PMID: 23950723; PubMed Central PMCID: PMC3738444.
4. Andrews SJ, Rothnagel JA. Emerging evidence for functional peptides encoded by short open reading frames. Nature reviews Genetics. 2014; 15(3):193-204. Epub 2014/02/12. doi: 10.1038/nrg3520 MID: 24514441.
5. Jousse C, Bruhat A, Carraro V, Urano F, Ferrara M, Ron D, et al. Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5'UTR. Nucleic acids research. 2001; 29(21):4341-51. Epub 2001/11/03. PMID: 11691921; PubMed Central PMCID: PMC60176.
6. Mueller PP, Hinnebusch AG. Multiple upstream AUG codons mediate translational control of GCN4. Cell. 1986; 45(2):201-7. Epub 1986/04/25. PMID: 3516411.
7. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. Journal of carcinogenesis. 2011; 10:20. Epub 2011/09/03. doi: 10.4103/1477-3163.83937 PMID: 21886458; PubMed Central PMCID: PMC3162670.
8. Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best practice & research Clinical endocrinology & metabolism. 2015; 29(4):569-80. Epub 2015/08/26. PMID: 26303084.
9. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M. The androgen receptor gene mutations database: 2012 update. Human mutation. 2012; 33(5):887-94. Epub 2012/02/16. doi: 10.1002/humu. 22046 PMID: 22334387.
10. Hiort O, Birnbaum W, Marshall L, Wunsch L, Werner R, Schroder T, et al. Management of disorders of sex development. Nature reviews Endocrinology. 2014; 10(9):520-9. Epub 2014/07/16. doi: 10.1038/ nrendo.2014.108 PMID: 25022812.
11. Deeb A, Mason C, Lee YS, Hughes IA. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clinical endocrinology. 2005; 63(1):56-62. Epub 2005/06/21. doi: 10.1111/j.1365-2265.2005.02298.x PMID: 15963062.
12. Jaaskelainen J. Molecular biology of androgen insensitivity. Molecular and cellular endocrinology. 2012; 352(1-2):4-12. Epub 2011/08/30. 10.1016/j.mce.2011.08.006. PMID: 21871529. doi: 10.1016/j. mce.2011.08.006
13. Mizokami A, Chang C. Induction of translation by the 5'-untranslated region of human androgen receptor mRNA. The Journal of biological chemistry. 1994; 269(41):25655-9. Epub 1994/10/14. PMID: 7929269.
14. Nakagawa S, Niimura Y, Gojobori T, Tanaka H, Miura K. Diversity of preferred nucleotide sequences around the translation initiation codon in eukaryote genomes. Nucleic acids research. 2008; 36(3):861-71. Epub 2007/12/19. doi: 10.1093/nar/gkm1102 PMID: 18086709; PubMed Central PMCID: PMC2241899.
15. Werner R, Holterhus PM. Androgen action. Endocrine development. 2014; 27:28-40. Epub 2014/09/ 24. doi: 10.1159/000363610 PMID: 25247642.
16. Audi L, Fernandez-Cancio M, Carrascosa A, Andaluz P, Toran N, Piro C, et al. Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development. The Journal of clinical endocrinology and metabolism. 2010; 95(4):1876-88. Epub 2010/ 02/13. doi: 10.1210/jc.2009-2146 PMID: 20150575.
17. Jenster G, van der Korput HA, Trapman J, Brinkmann AO. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. The Journal of biological chemistry. 1995; 270(13):7341-6. Epub 1995/03/31. PMID: 7706276.
18. Appari M, Werner R, Wunsch L, Cario G, Demeter J, Hiort O, et al. Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome. J Mol Med (Berl). 2009; 87(6):623-32. Epub 2009/03/31. doi: 10.1007/s00109-009-0462-3 PMID: 19330472.
19. Crocitto LE, Henderson BE, Coetzee GA. Identification of two germline point mutations in the 5'UTR of the androgen receptor gene in men with prostate cancer. The Journal of urology. 1997; 158(4):1599-601. Epub 1997/09/25. PMID: 9302181.
20. Peters KM, Edwards SL, Nair SS, French JD, Bailey PJ, Salkield K, et al. Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events. BMC cancer. 2012; 12:132. Epub 2012/04/05. doi: 10.1186/1471-2407-12-132 PMID: 22471922; PubMed Central PMCID: PMC3349557.
21. Wethmar K, Smink JJ, Leutz A. Upstream open reading frames: molecular switches in (patho)physiology. BioEssays: news and reviews in molecular, cellular and developmental biology. 2010; 32 (10):885-93. Epub 2010/08/21. PubMed Central PMCID: PMC3045505.
22. Holterhus PM, Bruggenwirth HT, Hiort O, Kleinkauf-Houcken A, Kruse K, Sinnecker GH, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. The Journal of clinical endocrinology and metabolism. 1997; 82(11):3584-9. Epub 1997/11/14. doi: 10.1210/jcem.82.11.4375 PMID: 9360511.
23. Zoppi S, Wilson CM, Harbison MD, Griffin JE, Wilson JD, McPhaul MJ, et al. Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation. The Journal of clinical investigation. 1993; 91(3):1105-12. Epub 1993/03/01. doi: 10.1172/JCI116269 PMID: 8450040; PubMed Central PMCID: PMC288066.
24. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91(4):1234-8. Epub 1994/02/15. PMID: 8108393; PubMed Central PMCID: PMC43131.
25. Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. The Journal of biological chemistry. 1991; 266(1):510-8. Epub 1991/01/05. PMID: 1985913.
26. van Royen ME, van Cappellen WA, de Vos C, Houtsmuller AB, Trapman J. Stepwise androgen receptor dimerization. Journal of cell science. 2012; 125(Pt 8):1970-9. Epub 2012/02/14. doi: 10.1242/jcs. 096792 PMID: 22328501.
27. Liegibel UM, Sommer U, Boercsoek I, Hilscher U, Bierhaus A, Schweikert HU, et al. Androgen receptor isoforms AR-A and AR-B display functional differences in cultured human bone cells and genital skin fibroblasts. Steroids. 2003; 68(14):1179-87. Epub 2003/12/04. PMID: 14643880.
28. Wang G, Guo X, Floros J. Differences in the translation efficiency and mRNA stability mediated by 5'-UTR splice variants of human SP-A1 and SP-A2 genes. American journal of physiology Lung cellular and molecular physiology. 2005; 289(3):L497-508. Epub 2005/05/17. doi: 10.1152/ajplung.00100. 2005 PMID: 15894557.
29. Ramalingam P, Palanichamy JK, Singh A, Das P, Bhagat M, Kassab MA, et al. Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing. RNA. 2014; 20(1):76-87. Epub 2013/11/15. doi: 10.1261/rna.041814.113 PMID: 24226766; PubMed Central PMCID: PMC3866646.