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B Gottlieb

Publications and source records attributed to B Gottlieb.

At least 19 recordsLinked to original sources
PubMed2001

Variable expressivity and mutation databases: The androgen receptor gene mutations database.

For over 50 years genetics has presumed that variations in phenotypic expression have, for the most part, been the result of alterations in genotype. The importance and value of mutation databases has been based on the premise that the same gene or allelic variation in a specific gene that has been proven to determine a specific phenotype, will always produce the same phenotype. However, recent evidence has shown that so called "simple" Mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained solely by a gene or allelic alteration. The AR gene mutations database now lists 25 cases where different degrees of androgen insensitivity are caused by identical mutations in the androgen receptor gene. In five of these cases the phenotypic variability is due to somatic mosaicism, that is, somatic mutations that occur in only certain cells of androgen-sensitive tissue. Recently, a number of other cases of variable expressivity have also been linked to somatic mosaicism. The impact of variable expressivity due to somatic mutations and mosaicism on mutation databases is discussed. In particular, the effect of an organism exhibiting genetic heterogeneity within its tissues, and the possibility of an organism's genotype changing over its lifetime, are considered to have important implications for mutation databases in the future.

Androgen-Insensitivity Syndrome↗
PubMed2001

Somatic mosaicism and variable expressivity.

For more than 50 years geneticists have assumed that variations in phenotypic expression are caused by alterations in genotype. Recent evidence shows that 'simple' mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained entirely by a gene or allelic alteration. In certain cases of androgen insensitivity syndrome caused by identical mutations in the androgen receptor gene, phenotypic variability is caused by somatic mosaicism, that is, somatic mutations that occur only in certain androgen-sensitive cells. Recently, more than 30 other genetic conditions that exhibit variable expressivity have been linked to somatic mosaicism. Somatic mutations have also been identified in diseases such as prostate and colorectal cancer. Therefore, the concept of somatic mutations and mosaicism is likely to have far reaching consequences for genetics, in particular in areas such as genetic counseling.

Animals↗
PubMed2001

A G577R mutation in the human AR P box results in selective decreases in DNA binding and in partial androgen insensitivity syndrome.

We have characterized a novel mutation of the human AR, G577R, associated with partial androgen insensitivity syndrome. G577 is the first amino acid of the P box, a region crucial for the selectivity of receptor/DNA interaction. Although the equivalent amino acid in the GR (also Gly) is not involved in DNA interaction, the residue at the same position in the ER (Glu) interacts with the two central base pairs in the PuGGTCA motif. Using a panel of 16 palindromic probes that differ in these base pairs (PuGNNCA) in gel shift experiments with either the AR DNA-binding domain or the full length receptor, we observed that the G577R mutation does not induce binding to probes that are not recognized by the wild-type AR. However, binding to the four PuGNACA elements recognized by the wild-type AR was affected to different degrees, resulting in an altered selectivity of DNA response element recognition. In particular, AR-G577R did not interact with PuGGACA palindromes. Modeling of the complex between mutant AR and PuGNACA motifs indicates that the destabilizing effect of the mutation is attributable to a steric clash between the C beta of Arg at position 1 of the P box and the methyl group of the second thymine residue in the TGTTCPy arm of the palindrome. In addition, the Arg side chain can interact with G or T at the next position (PuGCACA and PuGAACA elements, respectively). The presence of C is not favorable, however, because of incompatible charges, abrogating binding to the PuGGACA element. Transactivation of several natural or synthetic promoters containing PuGGACA motifs was drastically reduced by the G577R mutation. These data suggest that androgen target genes may be differentially affected by the G577R mutation, the first natural mutation characterized that alters the selectivity of the AR/DNA interaction. This type of mutation may thus contribute to the diversity of phenotypes associated with partial androgen insensitivity syndrome.

Amino Acid Sequence↗
PubMed2000

Interactions between androgen and estrogen receptors and the effects on their transactivational properties.

The physiological interplay of androgen and estrogen action in endocrine tissues is well recognized. The biochemical processes responsible for this interplay have yet to be fully defined. We have demonstrated that the androgen receptor (AR) and estrogen receptor-alpha (ERalpha) can interact directly using the yeast and mammalian two-hybrid systems. These interactions occurred between the C-terminal ERalpha ligand-binding domain and either the N-terminal AR transactivational domain or the full-length AR. Estrogen receptor-beta (ERbeta) did not interact with the AR. DNA cotransfection studies employing AR, ERalpha and ERbeta expression vectors and AR- or ER-reporter gene constructs were used to identify and measure potential functional effects of AR-ER interaction. Coexpression of ERalpha with AR decreased AR transactivation by 35%; coexpression of AR with ERalpha decreased ERalpha transactivation by 74%. Coexpression of AR and ERbeta did not significantly modulate AR or ERbeta transactivation. In summary, we have shown that specific domains of AR and ERalpha physically interact and have demonstrated the functional consequences of such interaction. These results may help explain the nature of the physiological interplay between androgens and estrogens.

Animals↗
PubMed2000

[Improving the quality of clinical interview teaching: evaluation of an intervention with medical students].

BACKGROUND: Quality of clinical interview is a key issue both for patient satisfaction and for diagnostic efficiency. Its adequacy relates to better clinical diagnosis treatment plans and patient compliance. AIM: To measure the quality of interviews performed by medical students in three Chilean medical schools before receiving specific training on the subject and to compare the scores obtained after introductory courses on interview. MATERIAL AND METHODS: The interviews were videotaped and then evaluated using an objective scale, that measures 33 skills grouped in six areas: opening, problem exploration, non verbal facilitation, interpersonal patient reaction and closing. The students were assigned to an experimental group that received an interactive workshop with role-plays, vignettes and videotape feedback, and to a non intervention group that received the usual bedside training on medical interviews. RESULTS: Both groups shared the same skill level before the training, with better scores on nonverbal, patient reaction and problem exploration, and worse ones on closing and interpersonal skills. Comparing pre and post-test results, the overall score improved in the experimental group (from 33.2 to 38.3, p = 0.002) and worsened among non intervened students. There were statistically significant changes for opening (p < 0.002), problem exploration (p < 0.05), non verbal facilitation (p < 0.0001) and closing (p < 0.0001). CONCLUSIONS: It is important to train students not only in specific knowledge contents but in the process of interview. This training should encourage the development of empathy and closing skills.

Education, Medical, Undergraduate↗
PubMed2000

[A new instrument for the evaluation of the medical profession. Use of the OSCE method].

BACKGROUND: Objective structured clinical examination has advantages over traditional oral examination of medical student. However, it is not routinely used in Chile. AIM: To describe the objective structured clinical examination system and report the results of its first use with Chilean medical students. MATERIAL AND METHODS: Thirteen interns ware evaluated at the end of their surgical rotation, using the objective structured clinical examination. Thirteen stations were structured for this examination: one for history taking, two for physical examination, four for problem solving and knowledge, one for radiological interpretation, one for instrumental recognition, one for skills and one for text comprehension. There were a total of 88 questions. RESULTS: All students exceeded 60% of requirements. Mean approval score was 73%. The higher score was 80% and the lower 61%. Ten students had a score over 70%. The method was well accepted by teachers and students. CONCLUSIONS: This first local experience with the objective structured clinical examination was successful.

Chile↗
PubMed1999

Androgen insensitivity.

The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen-AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene's transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones sometimes yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR-interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing.

Androgen-Insensitivity Syndrome↗
PubMed1999

Update of the androgen receptor gene mutations database.

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 309 to 374 during the past year. We have expanded the database by adding information on AR-interacting proteins; and we have improved the database by identifying those mutation entries that have been updated. Mutations of unknown significance have now been reported in both the 5' and 3' untranslated regions of the AR gene, and in individuals who are somatic mosaics constitutionally. In addition, single nucleotide polymorphisms, including silent mutations, have been discovered in normal individuals and in individuals with male infertility. A mutation hotspot associated with prostatic cancer has been identified in exon 5. The database is available on the internet (http://www.mcgill.ca/androgendb/), from EMBL-European Bioinformatics Institute (ftp.ebi.ac.uk/pub/databases/androgen), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

3' Untranslated Regions↗
PubMed1999

Analysis of exon 1 mutations in the androgen receptor gene.

Eleven mutations in exon 1 of the androgen receptor gene (AR) have been identified in 15 individuals with Androgen Insensitivity syndrome (AIS). Nine of the mutations yield a stop codon directly, or due to a frameshift, in individuals with complete AIS (CAIS). One individual with CAIS had three different mutations in exon 1: one is nominally silent (Glu 211; GAG 995 GAA); two are missense (Pro 390 Arg and Glu 443 Arg). Five unrelated individuals with either CAIS, partial AIS (PAIS) or mild AIS (MAIS) had GAG 995 GAA as their only alteration. This report almost doubles the number of exon 1 mutations stored in the AR Mutation Database, reinforces their highly predominant nonsense character, and identifies Pro 390 and/or Gln 443 as residues that are probably necessary for one or more specific functions of the AR's N-terminal transactivation domain.

Androgen-Insensitivity Syndrome↗
PubMed1999

Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions.

Structural changes in the androgen receptor (AR) are one of the causes of defective spermatogenesis. We screened the AR gene of 173 infertile men with impaired spermatogenesis and identified 3 of them, unrelated, who each had a single adenine-->guanine transition that changed codon 886 in exon 8 from methionine to valine. This mutation was significantly associated with the severely oligospermic phenotype and was not detected in 400 control AR alleles. Despite the location of this substitution in the ligand-binding domain (LBD) of the AR, neither the genital skin fibroblasts of the subjects nor transfected cell types expressing the mutant receptor had any androgen-binding abnormality. However, the mutant receptor had a consistently (approximately 50%) reduced capacity to transactivate each of 2 different androgen-inducible reporter genes in 3 different cell lines. Deficient transactivation correlated with reduced binding of mutant AR complexes to androgen response elements. Coexpression of AR domain fragments in mammalian and yeast two-hybrid studies suggests that the mutation disrupts interactions of the LBD with another LBD, with the NH2-terminal transactivation domain, and with the transcriptional intermediary factor TIF2. These data suggest that a functional element centered around M886 has a role, not for ligand binding, but for interdomain and coactivator interactions culminating in the formation of a normal transcription complex.

Adult↗
PubMed1998

The Androgen Receptor Gene Mutations Database.

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

Computer Communication Networks↗
PubMed1998

The Nuclear Receptor Resource: a growing family.

Last year, the original Glucocorticoid Receptor Resource was expanded into a comprehensive project: the Nuclear Receptor Resource (NRR, http:// nrr.georgetown.edu/nrr/nrr.html ). The NRR has since been offering comprehensive information on nuclear receptor structure and function, as well as general facts of interest to the scientific community on meetings, funding and employment opportunities. The project now includes individual resources as part of a network which integrates information on glucocorticoid, androgen, mineralocorticoid, thyroid hormone, Vitamin D and peroxisome-proliferator activated receptors. Many investigators have joined the NRR network by filling the Who is who? form available in the NRR home page. This has facilitated communication among scientists in the field and dissemination of data nor otherwise published. Because several investigators have contacted NRR authors over the past few months asking for advice and materials for educational purposes, we have recently decided to include in our project an educational resource on nuclear receptors termed the 'Graphics Library'. The input and suggestions of NRR users do shape the future direction of the project, so we encourage user to give us feedback.

Computer Communication Networks↗
PubMed1998

Evolutionary principles can guide nursing's future development.

Health care reform has resulted in a unique opportunity for nursing to develop and expand its role in future health care environments. We discuss why we think nursing's time has come, as well as the forces in present health care environments that threaten nursing's progress. We have used modern evolutionary principles to elucidate seven key conditions required for nursing to survive and flourish in the new health care environments. These conditions include the need for nurses to: be relevant; be accountable; be visible; be innovators; have a global impact; retain their uniqueness, while functioning in multidisciplinary settings; and be exceptionally competent, while striving for excellence.

Canada↗
PubMed1997

The androgen receptor gene mutations database.

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 212 to 272. We have expanded the database: (i) by adding a large amount of new data on somatic mutations in prostatic cancer tissue; (ii) by defining a new constitutional phenotype, mild androgen insensitivity (MAI); (iii) by placing additional relevant information on an internet site (http://www.mcgill.ca/androgendb/ ). The database has allowed us to examine the contribution of CpG sites to the multiplicity of reports of the same mutation in different families. The database is also available from EMBL (ftp.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker Pro or Word file (MC33@musica,mcgill.ca)

Computer Communication Networks↗
PubMed1996

The androgen receptor gene mutations database.

The current version of the androgen receptor (AR) gene mutations database is described. We have added (if available) data on the androgen binding phenotype of the mutant AR, the clinical phenotype of the affected persons, the family history and whether the pathogenicity of a mutation has been proven. Exonic mutations are now listed in 5'-->3' sequence regardless of type and single base pair changes are presented in codon context. Splice site and intronic mutations are listed separately. The database has allowed us to substantiate and amplify the observation of mutational hot spots within exons encoding the AR androgen binding domain. The database is available from EML (ftp://www.ebi.ac.uk/pub/databases/androgen) or as a Macintosh Filemaker file (MC33@musica.mcgill.ca).

Androgens↗
PubMed1994

Complete androgen insensitivity due to mutations in the probable alpha-helical segments of the DNA-binding domain in the human androgen receptor.

We describe different single-amino acid aberrations in the DNA-binding domain (DBD) of the human androgen receptor (hAR) in three families with complete androgen insensitivity. No additional alteration was found in the translated portion of each mutant gene. In one family, an in-frame 3 nt deletion removes codon 581-(or 582) and, thereby, one of two phenylalanines that invariably occupy adjacent positions in the N-terminal alpha-helical region of the DBD in the steroid/thyroid/vitamin D receptor superfamily. In the second, an in-frame 3 nt loss deletes Arg614, an invariant residue in the C-terminal alpha-helix of the DBD. In the third, a G-->A transition causes Arg614His. Following transient transfection of COS cells with each mutant AR plasmid, there is a normal concentration of specific androgen-binding activity that has a reduced ability to bind two types of androgen response element (ARE), and to transregulate an androgen-responsive human growth hormone reporter gene. In genital skin fibroblasts with delta Phe581 or Arg614His, androgen-binding, AR protein and AR mRNA are markedly reduced; in gonadal fibroblasts with delta Arg614, AR mRNA may be reduced. Our data substantiate the primary contributions of Phe581 and Arg614 to normal hAR-ARE binding, and expose important secondary effects of the mutations affecting each residue.

Amino Acid Sequence↗
PubMed1994

The androgen receptor gene mutations database.

The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca).

Databases, Factual↗