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      Novel and Recurrent Mutations in Patients with Androgen Insensitivity Syndromes

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          Background/Aims: Androgen insensitivity syndrome (AIS) caused by mutations within the androgen receptor gene represents a variety of phenotypes from females with 46,XY karyotype over individuals with ambiguous genitalia to infertile males. Methods: We studied 24 patients with AIS by sequencing androgen receptor gene. 19 of the investigated patients were affected by complete androgen insensitivity syndrome (CAIS) and 5 suffered from partial androgen insensitivity syndrome (PAIS). Results: So far we have detected 12 unreported mutations as well as 9 recurrent mutations (3 recurrent mutations were detected twice) in exons 2–8 of the androgen receptor gene. Three of the novel mutations cause a frameshift with subsequent premature termination and were found in patients with CAIS. These frameshifts were induced by single nucleotide deletion or insertion, or in one case by a 13-bp deletion, respectively. Another premature stop codon found in a CAIS patient results from an already reported nucleotide substitution in exon 5. Furthermore, in a CAIS patient we found a novel duplication of codon 788. All other mutations caused single base substitutions spread through exons 2–8 and were associated with CAIS or PAIS. Conclusions: We report a broad spectrum of different mutations within the AR gene leading to various manifestations of AIS. Apart from truncating mutations, a reliable genotype/phenotype correlation cannot be established. Therefore, modifying factors must be effective.

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          Most cited references 38

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          Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.

          The androgen receptor (AR) is a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation. Mutations or abnormal expression of AR in prostate cancer can play a key role in the process that changes prostate cancer from androgen-dependent to an androgen-independent stage. Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone, but not 10(-6) M hydroxyflutamide in human prostate cancer DU145 cells. Our data further indicated that ARA70 Will only slightly induce the transcriptional activity of other steroid receptors such as estrogen receptor, glucocorticoid receptor, and progesterone receptor in DU145 cells. Together, these data suggest that AR may need a specific coactivator(s) such as ARA70 for optimal androgen activity.
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            Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions.

            The androgen receptor (AR), a nuclear transcription factor, mediates male sexual differentiation, and its excessive action is associated with prostate cancer. We have characterized a negative regulatory domain in the AR hinge region, which interacted with filamin A (FLNa), an actin-binding cytoskeletal protein. FLNa interfered with AR interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Although full-length FLNa was predominantly cytoplasmic, a C-terminal 100-kDa fragment of FLNa colocalized with AR to the nucleus. This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2-activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre-initiation complex. This unanticipated role of FLNa adds to the growing evidence for the involvement of cytoskeletal proteins in transcription regulation.
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              Inhibition of nuclear hormone receptor activity by calreticulin.

              We have shown that a polypeptide of M(r) 60,000 (60K) that shares N-terminal homology with a calcium-binding protein, calreticulin, can bind to an amino-acid sequence motif, KXGFFKR, found in the cytoplasmic domains of all integrin alpha-subunits. The homologous amino-acid sequence, KXFFKR (where X is either G, A or V), is also present in the DNA-binding domain of all known members of the steroid hormone receptor family; amino acids in this sequence make direct contact with nucleotides in their DNA-responsive elements and are crucial for DNA binding. Here we show that both the 60K protein (p60), purified on a KLGFFKR-Sepharose affinity matrix, and recombinant calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element in a KXFFKR-sequence-specific manner. Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Our results indicate that calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                August 2005
                10 August 2005
                : 63
                : 6
                : 263-269
                aInstitut für Humangenetik der Otto-von-Guericke-Universität Magdeburg; bFrauenklinik für Gynäkologische Endokrinologie und Reproduktionsmedizin der RWTH Aachen; cInstitut für Humangenetik der Universität Giessen; dPraxis PD Dr. Uta Burck-Lehmann, Köln; eKinderklinik der Otto-von-Guericke-Universität Magdeburg; fInstitut für Humangenetik und Medizinische Biologie der Martin-Luther-Universität Halle-Wittenberg, Halle, Germany; gInstitut für Medizinische Biologie und Humangenetik der Medizinischen Universität Graz, Austria; hDepartment of Clinical Genetics, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK
                86018 Horm Res 2005;63:263–269
                © 2005 S. Karger AG, Basel

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                Page count
                Tables: 2, References: 56, Pages: 7
                Original Paper


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