TY - JOUR
T1 - Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid‐binding domain
AU - Murono, Koichi
AU - Mendonca, Berenice B.
AU - Arnhold, Ivo J.P.
AU - Rigon, Ana C.M.M.
AU - Migeon, Claude J.
AU - Brown, Terry R.
N1 - Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 1995
Y1 - 1995
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. © 1995 Wiley‐Liss, Inc.
AB - 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. © 1995 Wiley‐Liss, Inc.
KW - Androgen insensitivity
KW - Androgen receptor
KW - Human
KW - Mutation
KW - Testicular feminization
UR - http://www.scopus.com/inward/record.url?scp=0029120445&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029120445&partnerID=8YFLogxK
U2 - 10.1002/humu.1380060208
DO - 10.1002/humu.1380060208
M3 - Article
C2 - 7581399
AN - SCOPUS:0029120445
SN - 1059-7794
VL - 6
SP - 152
EP - 162
JO - Human mutation
JF - Human mutation
IS - 2
ER -