PubMed Health⌕ Search

Biomedical subjects

P Peterson

Publications and source records attributed to P Peterson.

At least 19 recordsLinked to original sources
PubMed1999

Isolation and characterization of the mouse Aire gene.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder characterized by Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have other clinical symptoms both within and outside the endocrine system, mainly as a result of autoimmunity against organ-specific autoantigens. The gene for APECED has recently been identified and termed AIRE (for AutoImmune REgulator). APECED is a model of organ-specific autoimmunity and isolation and characterization of the homologous mouse gene, Aire, will provide tools for dissection of the mechanisms underlying this human disorder and defining molecular pathways involved in organ-specific autoimmunity. We have isolated and completely sequenced the mouse Aire gene which is split into 14 exons over 13 kb and encodes a predicted protein of 552 amino acids. The predicted mouse and human AIRE proteins are 71% identical and contain motifs suggestive of a transcriptional regulator. Additional conserved motifs are emerging in the AIRE/Aire proteins including a nuclear localization signal, an "ASS" domain, and a "SAND" domain. The human and mouse AIRE promoters have conserved sites for several thymus-specific transcription factors and others important in hematopoesis, consistent with its expression in rare cells of the thymus medulla, lymph nodes, and fetal liver. We have mapped mouse Aire to mouse chromosome 10 by FISH, to the same region as Pwp2 and Pfkl, confirming synteny to the corresponding region of human chromosome 21.

3' Untranslated Regions↗
PubMed1999

Mutation analyses of North American APS-1 patients.

Autoimmune polyendocrinopathy syndrome type 1 (APS-1; MIM# 240300) is a rare autosomal recessively inherited disease characterised by destructive autoimmune diseases of endocrine glands. The gene responsible for APS-1, known as AIRE (for autoimmune regulator), was recently identified and contains motifs suggestive of a transcription regulator. To date, nine APS-1-associated mutations have been identified in the AIRE gene, including two common mutations R257X and 1094-1106del. In addition to these two mutations, we report seven novel mutations in 16 APS-1 patients from North America. We found that 1094-1106del and R257X were the most common mutations in this population of mixed geoethnic origin, accounting for 17/32 and 4/32 alleles, respectively. Haplotype analyses suggest that both are recurrent mutations, occurring on several different haplotypes with closely linked markers. All the novel mutations appear to be rare, occurring in only single APS-1 families. After examining all coding sequences and exon/intron boundaries of the AIRE gene, the other APS-1 allele remained unidentified in three patients. Genotype-phenotype correlations for APS-1 remain difficult, suggesting that other genetic or environmental factors, or both, influence the clinical presentation and disease progression in individual APS-1 patients.

DNA Mutational Analysis↗
PubMed1998

Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome.

The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.

Female↗
PubMed1998

Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis.

Exon trapping was performed from a partial cosmid, PAC, and P1 clone contig from human chromosome 21 between MX1 and 21qter to identify genes that may be involved in the pathogenesis of Down syndrome or several of the genetic diseases that map to chromosome 21q22.3. One 19-bp exon showed identity to three ESTs. The complete sequence of the EST clones, RT-PCR, and cDNA library screening were used to determine the full-length cDNA sequence of 2.2 kb with an open reading frame of 256-amino-acids. The putative 256-amino-acid peptide has homology with a hypothetical Caehorhabditis elegans protein of unknown function. Northern blot analysis of this gene, termed C21orf2 (chromosome 21 open reading frame 2), revealed two ubiquitously expressed mRNAs of 2.2 and 1.2 kb produced by use of alternative polyadenylation sites. Hybridization of the EST clones to a cosmid contig in chromosome 21q22.3 mapped C21orf2 just distal to PFKL, a critical mapping region for several genetic diseases. Comparison to publicly available genomic sequence, and additional data, revealed that the gene is split into seven exons over 10.5 kb, further refining the mapping position to only 1.2 kb distal to PFKL with the direction of transcription toward the centromere. The 5'UTR is contiguous with D21S400, and intron 2 contains a 52-bp VNTR polymorphism. Given its mapping position, C21orf2 is a candidate for involvement in disorders including autoimmune polyglandular disease type I (also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy or APECED) and the autosomal nonsyndromic deafness loci, DFNB8 and DFNB10. Mutation analysis using sequencing of RT-PCR and genomic DNA-derived PCR products, SSCP, and Southern and Northern blot analyses in APECED patients excluded C21orf2 as the gene for APECED.

Amino Acid Sequence↗
PubMed1998

The preoperative bleeding time test lacks clinical benefit: College of American Pathologists' and American Society of Clinical Pathologists' position article.

The major conclusions of this position article are as follows: (1) In the absence of a history of a bleeding disorder, the bleeding time is not a useful predictor of the risk of hemorrhage associated with surgical procedures. (2) A normal bleeding time does not exclude the possibility of excessive hemorrhage associated with invasive procedures. (3) The bleeding time cannot be used to reliably identify patients who may have recently ingested aspirin or nonsteroidal anti-inflammatory agents or those who have a platelet defect attributable to these drugs. The best preoperative screen to predict bleeding continues to be a carefully conducted clinical history that includes family and previous dental, obstetric, surgical, traumatic injury, transfusion, and drug histories. A history suggesting a possible bleeding disorder may require further evaluation; such an evaluation may include performance of the bleeding time test, as well as a determination of the platelet count, the prothrombin time, and the activated partial thromboplastin time. In the absence of a history of excessive bleeding, the bleeding time fails as a screening test and is, therefore, not indicated as a routine preoperative test.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

Autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED; also called APS-1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is characterized by two of the three major clinical symptoms that may be present: Addison's disease, and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. We have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes and fetal liver, and encodes a protein with two putative zinc fingers and other motifs suggestive of a transcriptional regulator. Seven mutations have been described to date, including R257X, the predominant Finnish and northern Italian APECED allele, which has also been observed in other patients of diverse origin on different haplotypes. A 13-bp deletion (1094-1106del) has also been observed in several patients of different geo-ethnic origin. The other described mutations appear to be rare. We present mutational analyses of the AIRE gene in ten Sardinian APECED families and show that there is a mutation, R139X, associated with one predominant haplotype unique to the Sardinian patients (18/20 independent alleles). The carrier frequency of R139X in Sardinia is 1.7%, giving an estimated population frequency of APECED of 1/14,400. Using linkage disequilibrium data, the estimated age of the R139X mutation is between 20 and 25 generations. A previously described 13-bp deletion was also observed on an allele of one patient. The identification of a single common Sardinian APECED mutation will facilitate its genetic diagnosis. Given the carrier frequency of R139X in the Sardinian population, AIRE may be implicated in the pathogenesis of other autoimmune diseases in the Sardinian population, particularly those affecting the endocrine system.

DNA Mutational Analysis↗
PubMed1998

Effect (or lack of it) of severe anemia on PT and APTT results.

Whether it is necessary to adjust the citrate volume in blood collection tubes for patients with anemia is unknown; however, the standard of care is not to adjust the volume. We compared the prothrombin time (PT) and activated partial thromboplastin time (APTT) test results of nonadjusted and adjusted citrate amounts in specimens from patients who are severely anemic. Samples were drawn into a 3.8% citrate volume, and if the hematocrit was less than 25% (0.25), additional samples were drawn into adjusted citrate tubes. The PT and APTT were run on 78 pairs of specimens, and the correlation coefficient was 0.98 for both assays. A statistically significant difference was noted between sample results collected in evacuated tubes in which the citrate volumes were adjusted to the hematocrit vs those in which it was not. However, when the difference between sets of values was plotted against the hematocrit, there was no correlation. There seems to be no need to change the standard practice for obtaining coagulation specimens into 3.8% citrate for patients who are anemic.

Adult↗
PubMed1998

Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM *240300, also called APS 1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is generally characterized by two of the three major clinical symptoms that may be present, Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have a number of other clinical symptoms including chronic gastritis, gonadal failure, and rarely, autoimmune thyroid disease and insulin-dependent diabetes mellitus. We and others have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes, and fetal liver and encodes a protein containing motifs suggestive of a transcriptional regulator, including two zinc finger motifs (PHD finger), a proline-rich region, and three LXXLL motifs. Six mutations, in cluding R257X, the predominant Finnish APECED allele, have been defined. R257X was also observed in non-Finnish APECED patients occurring on different chromosomal haplotypes suggesting different mutational origins. Here we present mutation analyses in an extended series of patients, mainly of Northern Italian origin. We have detected 12 polymorphisms, including one amino acid substitution, and two additional mutations, R203X and X546C, in addition to the previously described mutations, R257X, 1096-1097insCCTG, and a 13-bp deletion (1094-1106del). R257X was also the common mutation in the Northern Italian patients (10 of 18 alleles), and 1094-1106del accounted for 5 of 18 Northern Italian alleles. Both R257X and 1094-1106del were both observed in patients of four different geo-ethnic origins, and both were associated with multiple different haplotypes using closely flanking polymorphic markers showing likely multiple mutation events (six and four, respectively). The identification of common AIRE mutations in different APECED patient groups will facilitate its genetic diagnosis. In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system.

Female↗
PubMed1998

Vignettes of a pulmonary rehabilitation team.

A successful comprehensive pulmonary rehabilitation program depends on these key pieces: thorough planning, an experienced coordinator who is a patient advocate, a dedicated and supportive medical director, enthusiastic and committed team members, the use of program graduates as volunteers, and providing the essential components of pulmonary rehabilitation, which consist of assessment, patient training, exercise, psychosocial intervention, and follow-up. The patients are the most important members of the team. Their courage, dedication, and determination to make their quality of life the best it can be is truly an inspiration to all of us.

California↗
PubMed1998

Heart transplantation in patients with heparin-induced thrombocytopenia on the Novacor left ventricular assist system.

We report on two patients with development of heparin-induced thrombocytopenia with thrombosis while on the Novacor left ventricular assist system. Heart transplantation was successfully performed in both patients with heparin used for cardiopulmonary bypass after careful monitoring of heparin-associated antibodies. The approach to the patients' management and potential alternatives for anticoagulation are discussed.

Anticoagulants↗
PubMed1997

Immunochemical characterization of a novel mitochondrially located protein encoded by a nuclear gene within the DFNB8/10 critical region on 21q22.3.

A novel protein encoded by the C210RF2 gene in chromosomal locus 21q22.3 was characterized by immunochemistry. This chromosomal region is known to contain genes for human diseases such as non-syndromic autosomal recessive deafness (DFNB8/10) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Polyclonal murine antisera were produced against the multivalent peptides deduced from the amino acid sequence of the polypeptide. Immunological reactivity of the obtained antisera was tested with primary cells or established cell lines. On western blotting, the polyclonal sera recognized a single protein product of 25 Kd expressed in cell lines of epithelial and lymphoid origin. Subsequent immunochemistry of several human tissues indicated the ubiquitous expression of the protein. Immunofluorescence studies and co-staining with a mitochondrial-specific dye suggest the subcellular localization of the protein to mitochondria. Mitochondrial localization is also predicted by computer analysis of the polypeptide sequence. As deafness is known to be caused in some instances by defects in mitochondrial function, C210RF2 is a plausible candidate gene for DFNB8/10.

Amino Acid Sequence↗
PubMed1997

A linkage study of schizophrenia to markers within Xp11 near the MAOB gene.

A sex chromosome locus for psychosis has been considered on the basis of some sex differences in genetic risk and expression of illness, and an association with X-chromosome anomalies. Previous molecular genetic studies produced weak evidence for linkage of schizophrenia to the proximal short arm of the X-chromosome, while some other regions were not ruled out. Here we report an attempt to expand the Xp findings in: (i) a multicenter collaboration focusing on 92 families with a maternal pattern of inheritance (Study I), and (ii) an independent sample of 34 families unselected for parental mode of transmission (Study II). In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1). Significant allele sharing among affected sibling pairs was present at DXS7. In the second study, positive lod scores were observed at MAOB (highest of 2.16 at a theta of 0.05 for dominant and 1.64 at a theta of 0.00 for recessive models) and ALAS2 (the highest of 1.36 at a theta of 0.05 for a recessive model), with significant allele sharing (P = 0.003 and 0.01, respectively) at these two loci. These five markers are mapped within a small region of Xp11. Thus, although substantial regions of the X-chromosome have been investigated without evidence for linkage being found, a locus predisposing to schizophrenia in the proximal short arm of the X-chromosome is not excluded.

Chromosome Mapping↗
PubMed1997

Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group.

We have studied the sera from 304 patients with insulin-dependent diabetes mellitus (IDDM) for steroid 21-hydroxylase (P450c21) autoantibodies by an in vitro translation and immunoprecipitation assay. Autoantibodies to P450c21 were found in 7 patients with IDDM (2.3%). When the IDDM patients with P450c21 antibodies were analyzed for their HLA, 6 of them (86%) belonged to the HLA DQB1*0201-positive group. A strong correlation (r = 0.91, P < 0.001) of immunoprecipitation results was observed with adrenocortical autoantibodies detected by indirect immunofluorescence, indicating that the adrenal autoantibodies in patients with IDDM were anti-P450c21 autoantibodies. The levels of P450c21 autoantibodies were significantly higher (P < 0.05) in patients with IDDM than in 13 (9 P450c21 autoantibody positive) patients with Addison's disease. Although the occurrence of P450c21 antibodies in IDDM was relatively low, antibody-positive patients had high antibody levels and may have an ongoing subclinical process of adrenal autoimmunity.

Addison Disease↗
PubMed1997

Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8.

The Her-2/neu protooncogene is associated with malignant transformation and aggressive disease. Because of its overexpression in tumor cells and because it has been shown to be immunogenic, this protein represents an excellent target for T-cell immunotherapy. By identifying potential HLA-A2.1-binding peptides from the Her-2/neu sequence, peptides were selected as candidate T-cell epitopes. The immunogenicity of each peptide was evaluated by priming double transgenic mice expressing both the human (hu) CD8 and HLA-A2.1 molecules with synthetic peptides corresponding to these sequences. Because of the lack of interaction between murine CD8 and HLA-A2.1, expression of huCD8 on murine cells facilitates recognition of HLA molecules on human tumor cell lines. This led to the identification of two peptides that elicit an A2-restricted CTL response, one of which has not been previously identified. Both peptide-specific CTL populations were able to specifically lyse A2.1 and Her-2/neu expressing human tumor cells originating from a variety of tissues, demonstrating the utility of this murine model in identifying peptides presented by human cells. However, several Her-2/neu peptides previously reported to be immunogenic for human CTL were found not to be immunogenic in transgenic mice. The basis for these discrepancies is discussed.

Amino Acid Sequence↗
PubMed1997

Positional cloning of the APECED gene.

Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.

Amino Acid Sequence↗
PubMed1997

Immunoprecipitation of steroidogenic enzyme autoantigens with autoimmune polyglandular syndrome type I (APS I) sera; further evidence for independent humoral immunity to P450c17 and P450c21.

Three steroidogenic P450 cytochromes, steroid 17alpha-hydroxylase (P450c17), steroid 21-hydroxylase (P450c21) and side-chain cleavage enzyme (P450scc), have been described as autoantigens in APS I. In this study we report an immunoprecipitation assay for the detection of autoantibodies to these three enzymes using in vitro 35S-labelled antigens. Overall, 33 out of 46 (72%) patients with APS I had autoantibodies to at least one of the three proteins and each protein was recognized by patient sera with equal frequency. A higher rate of autoantibody positivity was observed in APS I patients with Addison's disease compared with patients without Addison's disease (85% versus 39%). All 11 patients with ovarian failure had anti-P450c17 or anti-P450scc antibodies. The immunoprecipitation results with P450c17, P450c21 and P450scc correlated well with the results obtained by immunoblotting assays. In addition, the steroidogenic enzymes 11beta-hydroxylase (P450c11beta), aromatase (P450arom), 3beta-hydroxysteroid dehydrogenase (3betaHSD) and adrenodoxin were studied by immunoprecipitation assay, but no reaction was found either with 46 APS I or with 26 healthy control sera. To study the suggested immunological cross-reactivity between P450c17 and P450c21 enzymes, nine APS I patient sera were preabsorbed with bacterially expressed P450c17 or P450c21 and subsequently used in immunoprecipitation assay. The absorption experiments clearly indicated that the preincubation inhibited only the reactivity of corresponding antigen, suggesting independent autoantibody response to the two enzymes. Our results suggest that the immune response to some but not to all steroidogenic enzymes is a specific feature of APS I that may be pathogenically significant.

Absorption↗