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Biomedical subjects

T Scholl

Publications and source records attributed to T Scholl.

At least 19 recordsLinked to original sources
PubMed2005

Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.

BACKGROUND: Genetic testing for hereditary cancer syndromes contributes to the medical management of patients who may be at increased risk of one or more cancers. BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer is one such widely used test. However, clinical testing methods with high sensitivity for deleterious mutations in these genes also detect many unclassified variants, primarily missense substitutions. METHODS: We developed an extension of the Grantham difference, called A-GVGD, to score missense substitutions against the range of variation present at their position in a multiple sequence alignment. Combining two methods, co-occurrence of unclassified variants with clearly deleterious mutations and A-GVGD, we analysed most of the missense substitutions observed in BRCA1. RESULTS: A-GVGD was able to resolve known neutral and deleterious missense substitutions into distinct sets. Additionally, eight previously unclassified BRCA1 missense substitutions observed in trans with one or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, are now classified as neutral. DISCUSSION: The methods combined here can classify as neutral about 50% of missense substitutions that have been observed with two or more clearly deleterious mutations. Furthermore, odds ratios estimated for sets of substitutions grouped by A-GVGD scores are consistent with the hypothesis that most unclassified substitutions that are within the cross-species range of variation at their position in BRCA1 are also neutral. For most of these, clinical reclassification will require integrated application of other methods such as pooled family histories, segregation analysis, or validated functional assay.

Amino Acid Sequence↗
PubMed2003

Application of haplotype pair analysis for the identification of hemizygous loci.

An expectation maximisation based prediction algorithm was created to identify unusual haplotypes in patient samples that may be caused by small intragenic deletions. In this approach, unphased SNP genotypes are compared to pairs of canonical haplotypes to identify potentially hemizygous regions. This method was successfully applied to identify five deletions in the 3' region of BRCA1.

Algorithms↗
PubMed2001

IGF-I, osteocalcin, and bone change in pregnant normotensive and pre-eclamptic women.

Pre-eclampsia is a pregnancy disorder of uncertain etiology that affects 5-10% of all pregnancies, with symptoms typically presenting around or after 20 wk gestation. We hypothesized that IGF-I, osteocalcin, and bone loss would be different among women with pre-eclampsia compared with normotensive pregnant women. There were 962 pregnant healthy women, aged 12-35, who were assessed at entry to care, at 28 wk, and at delivery for osteocalcin and IGF-I concentrations. Bone ultrasound was measured at entry to care and at 6 wk postpartum, whereas bone mineral density was measured by dual x-ray densitometry at delivery. There were 64 women (6.7%) among the women being followed who developed pre-eclampsia. In women with pre-eclampsia, IGF-I concentrations were 74% greater in the third trimester compared with the first trimester, whereas there was little change in osteocalcin concentrations. In contrast, normotensive women had an average increase of 43% in IGF-I concentrations accompanied by a 63% decline in osteocalcin concentrations. In women with pre-eclampsia, IGF-I and osteocalcin concentrations were significantly correlated (r = 0.48 and 0.43) at both the first and third trimester time points, but only in the third trimester among normotensive women (r = 0.27). The bone change difference between the two groups was not statistically significant. Women with pre-eclampsia appear to have an exaggerated IGF-I responsiveness compared with women who are normotensive; however, the strong correlation between IGF-I and osteocalcin in women with pre-eclampsia suggests that the IGF-I is able to retain its role as a local regulator of bone remodeling, as indicated by the osteocalcin concentrations.

Adult↗
PubMed2000

The BRCA2 genetic variant IVS7 + 2T-->G is a mutation.

Biochemical and genetic characterizations that support the conclusion that the variant BRCA2 IVS7 + 2T --> G represents a deleterious mutation are presented. RNA analysis from a breast cancer patient with BRCA2 IVS7 + 2T --> G showed that the productive message was produced from only one chromosome. A haplotype analysis confirmed that the intronic variant resides on the chromosome that does not produce the normal mRNA. Additionally, an RNA splicing product that deletes exon 7 was produced by the chromosome that carries BRCA2 IVS7 + 2T --> G. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249-287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. The experimental approach presented produces strong evidence of the presence of a deleterious mutation, because the contribution by both chromosomes to each RNA species analyzed was tracked using a coding region polymorphism as a marker. Furthermore, a single nucleotide polymorphism (SNP) haplotype analysis that confirms the location of the intronic variant and an associated family history that shows a high incidence of cancer supported these biochemical data.

5' Untranslated Regions↗
PubMed2000

Bone loss in adolescent and adult pregnant women.

OBJECTIVE: To determine the amount of change in bone ultrasound measures among pregnant adolescent girls and women and whether that change was associated with adolescence, maternal growth during pregnancy, limited weight gain during pregnancy, hypertension in pregnancy, or poor diet. METHODS: We used bone ultrasound measurements of attenuation and sound velocity to assess changes in quantitative ultrasound indices of 252 pregnant adolescent girls and women age 12-34 years. Bone ultrasound measurement of the os calcis was performed at 16 +/- 7 weeks' gestation (mean +/- standard deviation and 6 +/- 1 weeks postpartum. RESULTS: On average, the bone quantitative ultrasound index was 3.6% lower 6 weeks postpartum than at entry into care (P <.001). Nulliparous patients had significantly greater bone loss than did parous subjects. Still-growing adolescents had greater quantitative ultrasound index decreases than did grown women (-5.5% versus -1.9%, P <.02). Patients in the upper tertile of baseline quantitative ultrasound index lost more bone than did patients in the lower tertile (-5% versus 0.5%, P <.02). Pregravid weight, weight change during pregnancy, gynecologic age, and age at menarche predicted bone change in subgroups defined by parity or age; however, none of the differences in those variables were statistically significant. Greater dietary calcium intake, less physical activity, and pregnancy hypertension and preeclampsia were not associated with bone change. CONCLUSION: There has been inconsistent evidence of maternal bone loss during pregnancy. The findings of this study challenge the assumption that because of increased calcium absorption from the maternal intestine, no transitory bone loss occurs in pregnancy. The amount of bone loss among growing adolescents and nulliparous patients was consistent with the demands of fetal mineralization and the continued demands of the maternal skeleton during growth.

Adolescent↗
PubMed1999

BRCA1 IVS16+6T-->C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site.

Results and conclusions are presented that characterize BRCA1 IVS16+6T-->C as a deleterious mutation. BRCA1 transcripts from peripheral blood mononuclear cells of a breast cancer patient with the transition IVS16+6T-->C show the loss of a heterozygous base within codon 871. Additionally, an aberrant RNA splicing product which incorporates 69 bases of the 5' end of intron 16 at the junction of exons 16 and 17 is produced solely from the allele with IVS16+6T-->C. This insertion contains two in-frame stop codons and encodes a protein truncated at residue 1662 (plus 13 residues encoded by the intron). The aberrant transcript is specifically associated with the intronic variant since it was contained within the insertion. Furthermore, sequence analysis of the heterozygous base within codon 871 demonstrates that the two RNA products, productive mRNA and aberrantly spliced RNA, are contributed to exclusively by separate alleles. Finally, the aberrant transcript is produced by the activation of a cryptic splice site which has greater homology with the primate consensus splice sequence than the mutated exon 16 donor site.

Adult↗
PubMed1999

A characterization of genetic variants in BRCA1 intron 8 identifies a mutation and a polymorphism.

The biochemical and genetic characterizations of two variants that occur in BRCA1 intron 8 are presented. The variant IVS8+2T-->C induces an aberrant transcript that deletes exon 8. This exon-skipping deletion disrupts the open reading frame by juxtaposing exon 7 and exon 9 in the aberrant splice product. Theoretically, 50 abnormal residues from reading frame 2 are translated following exon 7 before a stop codon is encountered. The chromosomal contribution to the relevant RNA species was tracked using a silent polymorphism at codon 694 (serine AGC or AGT). Nucleotide sequencing of this polymorphic codon demonstrated that the aberrant transcript was derived solely from the chromosome encoding AGT. The normally spliced productive transcript also displayed loss of heterozygosity and was derived solely from the chromosome encoding AGC at codon 694. Also, a haplotype analysis using a breast cancer patient database showed that the chromosome bearing serine 694-AGT carried IVS8+2T-->C. A second more common variant, IVS8-58delT, was characterized as a polymorphism. Analysis of RNA from patient samples used the same silent polymorphism at codon 694 and showed that the normal message was derived from both chromosomes.

BRCA1 Protein↗
PubMed1998

The reproducibility of ultrasound bone measures in a triethnic population of pregnant adolescents and adult women.

We used bone ultrasound technology with its measurement of attenuation (broadband ultrasound attenuation [BUA] as dB/MHz) and sound velocity (speed of sound as m/s) for assessing the quantitative ultrasound index (QUI) summary measure in a triethnic population of 280 pregnant women. The study purpose was to describe the reproducibility of the ultrasound technology and determine if the correlations of age, weight, and ethnicity with the bone status measures in this population are consistent with the correlations of age, weight, and ethnicity that have been reported with other technologies that measure bone mass. We evaluated the first 280 women enrolled in our longitudinal study of lead turnover from maternal bone during pregnancy and lactation. Enrollees were pregnant, aged 12-29 years, and self-classified as black, white, or Hispanic. Bone ultrasound was measured twice at entry to prenatal care, which, on average, was at 14 weeks gestation. Reproducibility was described with intraclass correlations and the standard error of measurement. Age, weight, and ethnicity were associated with bone status measures using Spearman correlations and generalized linear models. The reproducibility of the summary bone measure, QUI, was high (96-97%). Variation in age and ethnicity did not alter reproducibility; however, the reproducibility of the attenuation measure (BUA as dB/MHz) lessened with increasing weight, declining from 95% to 89%. Since this attenuation is included in the summary QUI measure, there was a slight, and nonsignificant, decline in QUI reproducibility (from 97% to 96%) as women increased in size. There were no statistically significant differences in mean bone ultrasound measures according to age, where ages ranged from 12-29 years. Women who categorized themselves as black had, on average, an 8.5% greater QUI than did women who classified themselves as Hispanic or white. There were no significant pair-wise differences in mean ultrasound measures of bone between women classifying themselves as Hispanic or white. The use of ultrasound is a highly reproducible measure to assess bone characteristics in a population of pregnant adolescent and young adult women and its summary measure of bone mass is correlated with ethnic as well as body size characteristics.

Adolescent↗
PubMed1997

Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein.

CIITA is a positive regulator of class II major histocompatibility complex gene transcription that has been found to be defective in one of the five complementation groups of class II major histocompatibility complex-negative cell lines. Its N-terminal region is capable of activating transcription from a reporter gene when fused to a DNA binding domain. We have investigated the mechanism of transactivation mediated by the CIITA activation domain by studying its role in the process of transcription initiation and elongation. Specifically the altered specificity TBP (TATA box binding protein) assay has been used to analyze the response of the CIITA activation domain to mutations in TBP known to disrupt its interaction with its associated general factors. Transactivation by CIITA was extremely sensitive to a mutation in TBP that in yeast is known to abolish VP16-mediated transcription but leaves basal transcription unaffected. A TBP mutant defective in interaction with TBP-associated factor TAFII250 also failed to mediate transactivation through the CIITA activation domain. Certain interactions between TBP and general factors that are specifically required for acidic activation domains were also required for CIITA-mediated transactivation to reach its full potential. Finally, like VP16, CIITA was able to stimulate elongation of transcription. Overall the mechanism of transactivation by the human B-cell-specific CIITA is very similar to that mediated by the herpes virus transactivator VP16 in the ways that have been tested.

B-Lymphocytes↗
PubMed1997

Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5.

Two of the genes defective in the five complementation groups identified in the class II-negative bare lymphocyte syndrome or corresponding laboratory mutants have been cloned. One gene encodes a protein, RFX5, that is a member of the RFX family of DNA binding proteins. The other, CIITA, encodes a large protein with a defined acidic transcriptional activation domain; this protein does not interact with DNA. Expression plasmids encoding regions of RFX5 fused to the GAL4 DNA binding domain activated transcription from a reporter construct containing GAL4 sites in a cotransfection assay in the Raji human B cell line. However, these plasmids produced transcriptional activity in HeLa cells only in conjunction with interferon gamma stimulation, a condition in which expression of both CIITA and class II major histocompatibility complex surface proteins are induced. Furthermore, these plasmids were not active in RJ2.2.5, an in vitro mutagenized derivative of Raji in which both copies of CIITA are defective. Transcriptional activation by the RFX5 fusion protein could be restored in RJ2.2.5 by cotransfection with a CIITA expression plasmid. Finally, a direct interaction between RFX5 and CIITA was detected with the yeast two-hybrid and far-Western blot assays. Thus, RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.

B-Lymphocytes↗
PubMed1997

Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol.

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA), which is transformed by both, oxidation to 4-formyl-amino-antipyrine (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acetylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present study was to investigate whether cimetidine will alter the pharmacokinetics of the metabolites of metamizol due to cimetidine-induced inhibition of the metabolic transformation of 4-MAA. The study was carried out in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was administered 2 days prior to commencement of cimetidine therapy to all patients. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Blood samples for determination of metamizol metabolites were drown over 48 hours post dose. Drug assays for metamizol metabolites and cimetidine were performed using HPLC methods. The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetidine interacted with 4-MAA by increasing the systemic availability, prolonging the elimination half-life and decreasing the systemic clearance of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA to 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the decreased rates of production and the lower maximum concentrations of 4-FAA and 4-AA when metamizol was administered during cimetidine treatment (p < 0.05). No correlation was found between the decrease in the production rates of 4-FAA induced by cimetidine and the hydroxylation abilities of the patients, this suggesting that CYP2D6 is not involved in the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not proportional to the dose in the systemic availability only of 4-MAA, whereas the kinetics of the other metabolites changed proportionally to the increasing dose of metamizol.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

A zinc finger protein that represses transcription of the human MHC class II gene, DPA.

The proximal promoters of all MHC class II genes contain a sequence element, the 19-bp X box, that is conserved in both sequence and position. Extensive analysis using a wide variety of approaches has demonstrated that the integrity of the X box is essential for transcription initiation from all class II genes studied. However, the X box is now recognized to contain two subregions, termed X1 and X2. Radiolabeled oligonucleotides corresponding to the X2 box of the MHC class II genes DPA and DQB were used to screen B cell and T cell expression libraries. A novel cDNA, termed XBR (X box repressor), encoding a putative zinc finger protein that binds specifically to the DPA X2 box was isolated from a human T cell line. The XBR gene encodes a 7-kb message that is ubiquitously transcribed, although at higher levels in tissues of the lymphocytic compartment. Southern blots indicate that this gene is single copy in primates and contains regions that are highly divergent in other species. Overexpression of XBR in a B cell line resulted in a dramatic reduction of transcription from a reporter gene construct driven by the DPA promoter, but not from similar constructs with mutations in the X2 box. Similarly, overexpression of XBR reduced induction of reporter gene activity driven from the DPA promoter in HeLa cells treated with IFN-gamma. XBR may, therefore, mediate transcriptional repression, thus preventing inappropriate MHC class II expression. XBR function may in part explain the dominant trans-acting repression of MHC class II expression reported in cell fusion experiments.

Amino Acid Sequence↗