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Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction.
Mech Ageing Dev. 2004 Oct-Nov; 125(10-11):683-95.MA

Abstract

Partial androgen insensitivity with sex phenotype variation in two unrelated families was associated with missense mutations in the androgen receptor (AR) gene that disrupted the AR NH(2)-terminal/carboxy terminal interaction. Each mutation caused a single amino acid change within the region of the ligand-binding domain that forms activation function 2 (AF2). In one family, the mutation I737T was in alpha helix 4 and in the other F725L was between helices 3 and 4. Neither mutation altered androgen binding as determined by assays of mutant AR in the patient's cultured genital skin fibroblasts or of recombinant mutant receptors transfected into COS cells. In transient cotransfection assays in CV1 cells, transactivation with the AR mutants at low concentrations of DHT was reduced several fold compared with wild-type AR but increased at higher concentrations. Defects in NH(2)-terminal/carboxy terminal interactions were identified in mammalian two hybrid assays. In similar assays, there was reduced binding of the p160 coactivators TIF2/SRC2 and SRC1 to the mutant AR ligand binding domains (LBD). In the family with AR I737T, sex phenotype varied from severely defective masculinization in the proband to a maternal great uncle whose only manifestation of AIS was severe gynecomastia. He was fertile and passed the mutation to two daughters. The proband of the F725L family was also incompletely masculinized but was raised as a male while his half-sibling by a different father was affected more severely and reared as a female. These studies indicate that the function of an AR AF2 mutant in male development can vary greatly depending on the genetic background.

Authors+Show Affiliations

Department of Pediatrics, Laboratories for Reproductive Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7500, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15541764

Citation

Quigley, Charmian A., et al. "Partial Androgen Insensitivity With Phenotypic Variation Caused By Androgen Receptor Mutations That Disrupt Activation Function 2 and the NH(2)- and Carboxyl-terminal Interaction." Mechanisms of Ageing and Development, vol. 125, no. 10-11, 2004, pp. 683-95.
Quigley CA, Tan JA, He B, et al. Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction. Mech Ageing Dev. 2004;125(10-11):683-95.
Quigley, C. A., Tan, J. A., He, B., Zhou, Z. X., Mebarki, F., Morel, Y., Forest, M. G., Chatelain, P., Ritzén, E. M., French, F. S., & Wilson, E. M. (2004). Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction. Mechanisms of Ageing and Development, 125(10-11), 683-95.
Quigley CA, et al. Partial Androgen Insensitivity With Phenotypic Variation Caused By Androgen Receptor Mutations That Disrupt Activation Function 2 and the NH(2)- and Carboxyl-terminal Interaction. Mech Ageing Dev. 2004 Oct-Nov;125(10-11):683-95. PubMed PMID: 15541764.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction. AU - Quigley,Charmian A, AU - Tan,Jiann-an, AU - He,Bin, AU - Zhou,Zhong-xun, AU - Mebarki,Farida, AU - Morel,Yves, AU - Forest,Maguelone G, AU - Chatelain,Pierre, AU - Ritzén,E Martin, AU - French,Frank S, AU - Wilson,Elizabeth M, PY - 2004/11/16/pubmed PY - 2005/5/21/medline PY - 2004/11/16/entrez SP - 683 EP - 95 JF - Mechanisms of ageing and development JO - Mech Ageing Dev VL - 125 IS - 10-11 N2 - Partial androgen insensitivity with sex phenotype variation in two unrelated families was associated with missense mutations in the androgen receptor (AR) gene that disrupted the AR NH(2)-terminal/carboxy terminal interaction. Each mutation caused a single amino acid change within the region of the ligand-binding domain that forms activation function 2 (AF2). In one family, the mutation I737T was in alpha helix 4 and in the other F725L was between helices 3 and 4. Neither mutation altered androgen binding as determined by assays of mutant AR in the patient's cultured genital skin fibroblasts or of recombinant mutant receptors transfected into COS cells. In transient cotransfection assays in CV1 cells, transactivation with the AR mutants at low concentrations of DHT was reduced several fold compared with wild-type AR but increased at higher concentrations. Defects in NH(2)-terminal/carboxy terminal interactions were identified in mammalian two hybrid assays. In similar assays, there was reduced binding of the p160 coactivators TIF2/SRC2 and SRC1 to the mutant AR ligand binding domains (LBD). In the family with AR I737T, sex phenotype varied from severely defective masculinization in the proband to a maternal great uncle whose only manifestation of AIS was severe gynecomastia. He was fertile and passed the mutation to two daughters. The proband of the F725L family was also incompletely masculinized but was raised as a male while his half-sibling by a different father was affected more severely and reared as a female. These studies indicate that the function of an AR AF2 mutant in male development can vary greatly depending on the genetic background. SN - 0047-6374 UR - https://www.unboundmedicine.com/medline/citation/15541764/Partial_androgen_insensitivity_with_phenotypic_variation_caused_by_androgen_receptor_mutations_that_disrupt_activation_function_2_and_the_NH_2___and_carboxyl_terminal_interaction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0047-6374(04)00160-5 DB - PRIME DP - Unbound Medicine ER -