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Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain.
Hum Mutat. 1995; 6(2):152-62.HM

Abstract

Mutations of the human androgen receptor gene were identified in five subjects from four families with androgen insensitivity syndrome. Individual exons of the androgen receptor gene were amplified by the polymerase chain reaction from genomic DNA and screened for sequence-dependent differences in their melting characteristics by denaturing gradient gel electrophoresis. DNA fragments from exons with altered mobility were sequenced. Four different single nucleotide base substitutions were found within exons 5, 6, and 7 encoding the steroid-binding domain of the androgen receptor. In one subject with ambiguous genitalia, amino acid residue 763 was changed from tyrosine to cysteine (TAC-->TGC; Y763C). Four subjects, including two siblings, had complete androgen insensitivity. In one subject, residue 779 was changed from arginine to tryptophan (CGC-->TGG; R779W), another subject (M807V) had a substitution of valine (GTG) for methionine (ATG) residue at position 807, and the two siblings (R855C) had a mutation in residue 855 changing arginine (CGC) to cysteine (TGC). Binding of the synthetic androgen ligand, methyltrienolone (R1881), by the mutant receptor Y763C was decreased by 54% compared to the normal receptor. Transcriptional activation of a mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene by AR mutant Y763C was negligible at 0.1 nM R1881 and only 55% at 10 nM R1881 when compared to the maximal response with the normal AR, as assessed by CAT activity. Mutant M807V retained only 22% of normal R1881 binding and mutant R855C was unable to bind the steroid. In accordance with the steroid binding, transcriptional activation of MMTV-CAT by M807V rose to only 26% of control in the presence of 10 nM R1881, a concentration at which R855C remained functionally inactive. In summary, missense mutations within the exons of the androgen receptor gene encoding the steroid-binding domain of the receptor are common causes of both partial and complete forms of androgen insensitivity syndrome.

Authors+Show Affiliations

Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paolo, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7581399

Citation

Murono, K, et al. "Human Androgen Insensitivity Due to Point Mutations Encoding Amino Acid Substitutions in the Androgen Receptor Steroid-binding Domain." Human Mutation, vol. 6, no. 2, 1995, pp. 152-62.
Murono K, Mendonca BB, Arnhold IJ, et al. Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain. Hum Mutat. 1995;6(2):152-62.
Murono, K., Mendonca, B. B., Arnhold, I. J., Rigon, A. C., Migeon, C. J., & Brown, T. R. (1995). Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain. Human Mutation, 6(2), 152-62.
Murono K, et al. Human Androgen Insensitivity Due to Point Mutations Encoding Amino Acid Substitutions in the Androgen Receptor Steroid-binding Domain. Hum Mutat. 1995;6(2):152-62. PubMed PMID: 7581399.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain. AU - Murono,K, AU - Mendonca,B B, AU - Arnhold,I J, AU - Rigon,A C, AU - Migeon,C J, AU - Brown,T R, PY - 1995/1/1/pubmed PY - 1995/1/1/medline PY - 1995/1/1/entrez SP - 152 EP - 62 JF - Human mutation JO - Hum Mutat VL - 6 IS - 2 N2 - Mutations of the human androgen receptor gene were identified in five subjects from four families with androgen insensitivity syndrome. Individual exons of the androgen receptor gene were amplified by the polymerase chain reaction from genomic DNA and screened for sequence-dependent differences in their melting characteristics by denaturing gradient gel electrophoresis. DNA fragments from exons with altered mobility were sequenced. Four different single nucleotide base substitutions were found within exons 5, 6, and 7 encoding the steroid-binding domain of the androgen receptor. In one subject with ambiguous genitalia, amino acid residue 763 was changed from tyrosine to cysteine (TAC-->TGC; Y763C). Four subjects, including two siblings, had complete androgen insensitivity. In one subject, residue 779 was changed from arginine to tryptophan (CGC-->TGG; R779W), another subject (M807V) had a substitution of valine (GTG) for methionine (ATG) residue at position 807, and the two siblings (R855C) had a mutation in residue 855 changing arginine (CGC) to cysteine (TGC). Binding of the synthetic androgen ligand, methyltrienolone (R1881), by the mutant receptor Y763C was decreased by 54% compared to the normal receptor. Transcriptional activation of a mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene by AR mutant Y763C was negligible at 0.1 nM R1881 and only 55% at 10 nM R1881 when compared to the maximal response with the normal AR, as assessed by CAT activity. Mutant M807V retained only 22% of normal R1881 binding and mutant R855C was unable to bind the steroid. In accordance with the steroid binding, transcriptional activation of MMTV-CAT by M807V rose to only 26% of control in the presence of 10 nM R1881, a concentration at which R855C remained functionally inactive. In summary, missense mutations within the exons of the androgen receptor gene encoding the steroid-binding domain of the receptor are common causes of both partial and complete forms of androgen insensitivity syndrome. SN - 1059-7794 UR - https://www.unboundmedicine.com/medline/citation/7581399/Human_androgen_insensitivity_due_to_point_mutations_encoding_amino_acid_substitutions_in_the_androgen_receptor_steroid_binding_domain_ L2 - https://doi.org/10.1002/humu.1380060208 DB - PRIME DP - Unbound Medicine ER -