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Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro.
Exp Clin Endocrinol Diabetes. 2005 Sep; 113(8):457-63.EC

Abstract

The majority of genetic variations in the androgen receptor (AR) gene are point mutations leading to impairment of the DNA- or hormone-binding domains. The N-terminus encoded by the first exon of the AR-gene usually harbors disruptive mutations associated with complete androgen insensitivity syndrome (CAIS) while missense mutations related with partial androgen insensitivity syndrome (PAIS) are seemingly rare. We present a 46,XY male with scrotal hypospadias in whom we detected a S432 F point mutation within the N-terminus. Transient transfections of an AR expression plasmid carrying the S432 F mutation using Chinese Hamster Ovary (CHO) cells revealed a significant partial reduction in transactivation of the co-transfected androgen responsive (ARE) (2)TATA luciferase reporter gene thus confirming PAIS. In two further 46, XY patients with slight to moderate virilization defects, we detected an S411 N mutation, and a 9 base pair deletion leading to the loss of amino acids 409 to 411 (L-A-S), respectively. These mutations did not compromise AR-function under the chosen experimental settings. The S432 F-patient supports particular significance of the AR-N-terminus for mild forms of AIS while the functional role of the two further mutations remains unclear. The N-terminus is a species-specific AR-domain possibly also involved in contributing to target tissue selectivity of AR-actions via mediating co-regulator interactions. Therefore, mild molecular defects of the AR-N-terminus may not necessarily inhibit general transactivation properties using currently established reporter gene models.

Authors+Show Affiliations

Department of Pediatrics, University-Hospital of Schleswig-Holstein, Campus Lübeck, Germany.No affiliation info availableNo affiliation info availableNo 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

16151980

Citation

Holterhus, P-M, et al. "Mutations in the Amino-terminal Domain of the Human Androgen Receptor May Be Associated With Partial Androgen Insensitivity and Impaired Transactivation in Vitro." Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association, vol. 113, no. 8, 2005, pp. 457-63.
Holterhus PM, Werner R, Struve D, et al. Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro. Exp Clin Endocrinol Diabetes. 2005;113(8):457-63.
Holterhus, P. M., Werner, R., Struve, D., Hauffa, B. P., Schroeder, C., & Hiort, O. (2005). Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro. Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association, 113(8), 457-63.
Holterhus PM, et al. Mutations in the Amino-terminal Domain of the Human Androgen Receptor May Be Associated With Partial Androgen Insensitivity and Impaired Transactivation in Vitro. Exp Clin Endocrinol Diabetes. 2005;113(8):457-63. PubMed PMID: 16151980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro. AU - Holterhus,P-M, AU - Werner,R, AU - Struve,D, AU - Hauffa,B P, AU - Schroeder,C, AU - Hiort,O, PY - 2005/9/10/pubmed PY - 2006/1/7/medline PY - 2005/9/10/entrez SP - 457 EP - 63 JF - Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association JO - Exp Clin Endocrinol Diabetes VL - 113 IS - 8 N2 - The majority of genetic variations in the androgen receptor (AR) gene are point mutations leading to impairment of the DNA- or hormone-binding domains. The N-terminus encoded by the first exon of the AR-gene usually harbors disruptive mutations associated with complete androgen insensitivity syndrome (CAIS) while missense mutations related with partial androgen insensitivity syndrome (PAIS) are seemingly rare. We present a 46,XY male with scrotal hypospadias in whom we detected a S432 F point mutation within the N-terminus. Transient transfections of an AR expression plasmid carrying the S432 F mutation using Chinese Hamster Ovary (CHO) cells revealed a significant partial reduction in transactivation of the co-transfected androgen responsive (ARE) (2)TATA luciferase reporter gene thus confirming PAIS. In two further 46, XY patients with slight to moderate virilization defects, we detected an S411 N mutation, and a 9 base pair deletion leading to the loss of amino acids 409 to 411 (L-A-S), respectively. These mutations did not compromise AR-function under the chosen experimental settings. The S432 F-patient supports particular significance of the AR-N-terminus for mild forms of AIS while the functional role of the two further mutations remains unclear. The N-terminus is a species-specific AR-domain possibly also involved in contributing to target tissue selectivity of AR-actions via mediating co-regulator interactions. Therefore, mild molecular defects of the AR-N-terminus may not necessarily inhibit general transactivation properties using currently established reporter gene models. SN - 0947-7349 UR - https://www.unboundmedicine.com/medline/citation/16151980/Mutations_in_the_amino_terminal_domain_of_the_human_androgen_receptor_may_be_associated_with_partial_androgen_insensitivity_and_impaired_transactivation_in_vitro_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-2005-865770 DB - PRIME DP - Unbound Medicine ER -