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Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome.
Hum Mutat. 2006 Mar; 27(3):291.HM

Abstract

Mutations in the androgen receptor (AR) gene result in androgen insensitivity syndrome (AIS). We have identified five novel mutations that result in a complete loss in AR function and are associated with complete AIS. The mutations span all three AR major functional domains. In two cases, the loss of AR function could be explained on the basis of the current knowledge of AR molecular structure and function. N-terminal mutation c.256C>T (p.Gln86X) leads to an early stop codon and abolishes all DNA and ligand binding. The DNA-binding domain mutation c.1685G>A (p.Cys562Tyr) is located in the N-terminal part of the first zinc finger; a mutation in this position is likely to impair the association of the mutated AR with the androgen response element of target genes. The splice site mutation at intron 2/exon 3 junction (c.1766-1G>A) is shown to lead to c.1765_1766 ins69 (p.[Gly589_Lys590ins23;Gly589Glu]). The two novel ligand-binding domain mutations identified were recreated by site-directed mutagenesis. Both mutations c.2171G>T (p.Gly724Val) and c.2435T>C (p.Leu812Pro) abolished AR ligand binding and severely impaired AR mediated transactivation. Residue p.Gly724 is located in the ligand binding domain, between helices 3 and 4. This region is known to be involved not only in ligand binding but also in AR N/C-terminal interactions. The mutation p.Leu812Pro is located in the C-terminal end of helix 8. This domain is highly conserved and critical for ligand binding. This study extends current understanding of AR mutations associated with CAIS.

Authors+Show Affiliations

Department of Paediatrics, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom. jarmo.jaaskelainen@uku.fiNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16470553

Citation

Jääskeläinen, Jarmo, et al. "Five Novel Androgen Receptor Gene Mutations Associated With Complete Androgen Insensitivity Syndrome." Human Mutation, vol. 27, no. 3, 2006, p. 291.
Jääskeläinen J, Mongan NP, Harland S, et al. Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome. Hum Mutat. 2006;27(3):291.
Jääskeläinen, J., Mongan, N. P., Harland, S., & Hughes, I. A. (2006). Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome. Human Mutation, 27(3), 291.
Jääskeläinen J, et al. Five Novel Androgen Receptor Gene Mutations Associated With Complete Androgen Insensitivity Syndrome. Hum Mutat. 2006;27(3):291. PubMed PMID: 16470553.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome. AU - Jääskeläinen,Jarmo, AU - Mongan,Nigel P, AU - Harland,Sharon, AU - Hughes,Ieuan A, PY - 2006/2/14/pubmed PY - 2006/8/3/medline PY - 2006/2/14/entrez SP - 291 EP - 291 JF - Human mutation JO - Hum Mutat VL - 27 IS - 3 N2 - Mutations in the androgen receptor (AR) gene result in androgen insensitivity syndrome (AIS). We have identified five novel mutations that result in a complete loss in AR function and are associated with complete AIS. The mutations span all three AR major functional domains. In two cases, the loss of AR function could be explained on the basis of the current knowledge of AR molecular structure and function. N-terminal mutation c.256C>T (p.Gln86X) leads to an early stop codon and abolishes all DNA and ligand binding. The DNA-binding domain mutation c.1685G>A (p.Cys562Tyr) is located in the N-terminal part of the first zinc finger; a mutation in this position is likely to impair the association of the mutated AR with the androgen response element of target genes. The splice site mutation at intron 2/exon 3 junction (c.1766-1G>A) is shown to lead to c.1765_1766 ins69 (p.[Gly589_Lys590ins23;Gly589Glu]). The two novel ligand-binding domain mutations identified were recreated by site-directed mutagenesis. Both mutations c.2171G>T (p.Gly724Val) and c.2435T>C (p.Leu812Pro) abolished AR ligand binding and severely impaired AR mediated transactivation. Residue p.Gly724 is located in the ligand binding domain, between helices 3 and 4. This region is known to be involved not only in ligand binding but also in AR N/C-terminal interactions. The mutation p.Leu812Pro is located in the C-terminal end of helix 8. This domain is highly conserved and critical for ligand binding. This study extends current understanding of AR mutations associated with CAIS. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/16470553/Five_novel_androgen_receptor_gene_mutations_associated_with_complete_androgen_insensitivity_syndrome_ L2 - https://doi.org/10.1002/humu.9405 DB - PRIME DP - Unbound Medicine ER -