Biomedical subjects

Ismo Ulmanen

Publications and source records attributed to Ismo Ulmanen.

11 recordsLinked to original sources

PubMed2006

Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

Animals↗

PubMed2006

Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients.

Mutations in the autoimmune regulator (AIRE) gene cause a recessive Mendelian disorder autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). APS-1 patients develop multiorgan autoimmune diseases including type 1 diabetes (prevalence 12%). The AIRE protein controls the central tolerance induction in the thymus by regulating the expression levels of tissue-specific peripheral antigens, such as insulin. We hypothesized that the insulin gene (INS) polymorphisms together with the AIRE variations may predispose individuals to diabetes. The role of the AIRE gene was tested both independently and on the condition of the INS risk genotype in the Finnish type 1 diabetes sample. A total of 733 type 1 diabetic cases and 735 age- and sex-matched healthy controls were used in the analysis. Five common single nucleotide polymorphisms (SNPs) in the AIRE gene were selected from the public database (dbSNP). The -23HphI polymorphism was used as a surrogate marker for the INS gene promoter repeat. The five genotyped SNPs in the AIRE gene showed no evidence of association with type 1 diabetes. As expected, the INS gene polymorphism -23HphI was significantly associated with susceptibility to type 1 diabetes (P=6.8 x 10(-12), chi(2) test). When the subclass of patients carrying the homozygote genotype of the INS gene was used in the analysis, the AIRE polymorphisms showed no association with the disease. In conclusion, the AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population.

Adult↗

PubMed2006

The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin alpha molecules.

Autoimmune regulator (AIRE) is a transcriptional regulator involved in establishing immunological self-tolerance. Mutations in the AIRE gene lead to the development of the autosomal, recessively inherited, organ-specific autoimmune disease, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). The AIRE protein is mainly localized in the cell nucleus where it is associated with nuclear bodies. The N-terminal part of AIRE has been previously shown to mediate nuclear localization of the protein. However, the functional nuclear localization signal (NLS) and nuclear import mechanisms of AIRE have not been identified. We show that, although the amino-acid sequence of AIRE contains a potential bipartite NLS consisting of amino acids 110-114 and 131-133, only the latter part constitutes a functional NLS. Furthermore, we show by in vitro binding assays that AIRE interacts with multiple members of the nuclear transport receptor importin alpha family, mainly alpha1, alpha3, and alpha5, and that these interactions depend on the intactness of the Arg-Lys-rich NLS of AIRE. In addition, we found that AIRE binds to the 'minor' NLS-binding site of importin alpha3 and alpha5 proteins consisting of the C-terminal armadillo repeats 7-9. Our findings strongly suggest that the nuclear import of AIRE is mediated by the classical importin alpha/beta pathway through binding to several importin alpha family members.

Amino Acid Sequence↗

PubMed2006

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population.

OBJECTIVE: To determine the Irish prevalence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), the AIRE mutations involved and clinical features of this population. METHODS: All patients were identified through paediatricians and endocrinologists in Ireland. Patients were invited to attend a multidisciplinary clinic. RESULTS: Thirty-one patients (2-56 years), 18 female, were identified from 19 families giving an Irish prevalence of 1:130,000. Twenty-six patients had hypoparathyroidism, 21 had adrenal insufficiency (AI) and 10 of 16 had ovarian failure. Three affected patients have died. Many with hypoparathyroidism were resistant to 1-alpha-vitamin D. Two needed daily PTH injections. Mineralocorticoid deficiency as the first manifestation of AI was common. Chronic intra-oral candidiasis affected 25 patients and three had leukoplakia. Two had keratoconjuntivitis. Of 22 with AIRE gene analysis, three different mutations were identified, one of which is novel. CONCLUSION: APECED is rare in Ireland. We saw a significant amount of non-endocrine disease but no ectodermal dystrophy. AIRE gene analysis reassured many siblings and identified individuals with APECED prior to any symptoms.

Adolescent↗

PubMed2005

Triallelic patterns in STR loci used for paternity analysis: evidence for a duplication in chromosome 2 containing the TPOX STR locus.

We report triallelic patterns in several short tandem repeat (STR) loci revealed by routine paternity testing using the commercial AMPFlSTR Profiler and AMPFlSTR SGMplus kits. One case where the TPOX-locus (2p25.3) produced three peaks from the blood sample of a child was analysed further. Quantitative polymerase chain reaction (QPCR) and STR typing of the DNAs of the family trio revealed a large (>1.59 Mb) duplication flanking the TPOX-locus in chromosome 2 in both the mother and child. The implications of such genetic anomalies for paternity testing are discussed.

Child↗

PubMed2005

Monogenic autoimmune diseases - lessons of self-tolerance.

The molecular defects recently identified in the rare monogenic autoimmune diseases (AIDs) have pinpointed critical steps in the pathways that contribute to the development of normal immune responses and self-tolerance. Recent studies of autoimmune polyendocrinopathy syndrome type 1, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, IL-2 receptor alpha-chain deficiency, and, in particular, their corresponding mouse models, have revealed the details of the molecular mechanisms of normal immune tolerance, and exposed how defects in these mechanisms result in human autoimmunity. In addition to a deeper understanding of the immune system, detailed molecular characterization of monogenic AIDs will help us to understand the mechanisms behind common polygenic AIDs and, furthermore, to develop novel therapies and intervention strategies to treat them.

Animals↗

PubMed2005

Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by a variable combination of organ-specific autoimmune diseases. Studies on AIRE-deficient mice suggest that AIRE is an important factor in the establishment and maintenance of self-tolerance. The AIRE protein contains several structural domains often found in transcriptional regulators and functions as a transcriptional transactivator in vitro. To date, more than 50 patient mutations have been identified in the coding region of the AIRE gene. So far, APECED has been reported to be inherited in an autosomal recessive manner. However, in contrast to all other AIRE mutations, a novel mutation c.682T>G (p.G228W) in the DNA-binding and/or multimerization domain SAND was recently described to be inherited in a dominant fashion. We analyzed the effects of mutant AIRE proteins containing the patient mutations c.682T>G (p.G228W) and c.755C>T (p.P252L) located in the SAND domain on the properties of the wild-type AIRE in a heterozygous situation in vitro. In addition to the patient mutations, we analyzed the effects of a double mutation [c.727A>G;c.728A>C;c.739C>G;c740G>C] (p.K243A;R247A) of positively charged amino acids in the SAND domain. Of the mutants studied, only c.682T>G (p.G228W) mutant changed the subcellular localization and in addition severely disrupted the transactivating capacity of the wild-type AIRE. Our results indicate that the c.682T>G (p.G228W) mutant AIRE protein acts with a dominant negative effect by binding to the wild-type AIRE, thus preventing the protein from forming the complexes needed for transactivation.

Animals↗

PubMed2004

APECED-causing mutations in AIRE reveal the functional domains of the protein.

A defective form of the AIRE protein causes autoimmune destruction of target organs by disturbing the immunological tolerance of patients with a rare monogenic disease, autoimmune polyendocrinopathy (APE)-candidiasis (C)-ectodermal dystrophy (ED), APECED. Recently, experiments on knockout mice revealed that AIRE controls autoimmunity by regulating the transcription of peripheral tissue-restricted antigens in thymic medullary epithelial cells. Thus, AIRE provides a unique model for molecular studies of organ-specific autoimmunity. In order to analyze the molecular and cellular consequences of 16 disease-causing mutations in vitro, we studied the subcellular localization, transactivation capacity, homomultimerization, and complex formation of several mutant AIRE polypeptides. Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments. While the PHD zinc fingers were necessary for the transactivation capacity of AIRE, other regions of AIRE also modulated this function. Consequently, most of the mutations decreased transactivation. The HSR domain was responsible for the homomultimerization activity of AIRE; all the missense mutations of the HSR and the SAND domains decreased this activity, but those in other domains did not. The AIRE protein was present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturbed the formation of these complexes. In conclusion, we propose an in vitro model in which AIRE transactivates transcription through heteromeric molecular interactions that are regulated by homomultimerization and conditional localization of AIRE in the nucleus or in the cytoplasm.

Amino Acid Sequence↗

PubMed2003

Catechol-O-methyl transferase (COMT) inhibitors in patients with Parkinson's disease: is COMT genotype a useful indicator of clinical efficacy?

In clinical practice, two potent and selective catechol-O-methyl transferase (COMT) inhibitors are available for the control of motor fluctuation in patients with Parkinson's disease. However, because of the complexity of fluctuating motor symptoms, it is difficult to evaluate the clinical efficacy of COMT inhibitors in each individual. Therefore, an objective factor predicting the clinical efficacy of COMT inhibitors is needed. Individual variation in COMT activity is regulated by a single nucleotide of the COMT gene on the long arm of chromosome 22. Therefore, there could be a correlation between COMT genotype and the clinical efficacy of COMT inhibitors. Three double-blind studies evaluating the efficacy of a single or repeated doses of a COMT inhibitor failed to find significant difference in the improvement in the duration of daily 'on' time and degree of motor abilities between patients with different COMT genotypes. Furthermore, there were no significant differences in the severity and frequency of dopaminergic adverse effects between patients with different COMT genotypes. These data suggest that the COMT genotype is not a major factor in deciding the clinical efficacy of COMT inhibitors.

Animals↗

PubMed2002

The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder.

Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. The pathogenetic mechanisms of mulibrey nanism are unknown. We have used transiently transfected cells and antibodies raised against the predicted TRIM37 protein to characterize the TRIM37 gene product and to determine its intracellular localization. We show that the human TRIM37 cDNA encodes a peroxisomal protein with an apparent molecular weight of 130 kD. Peroxisomal localization is compromised in mutant protein representing the major Finnish TRIM37 mutation but is retained in the protein representing the minor Finnish mutation. Colocalization of endogenous TRIM37 with peroxisomal markers was observed by double immunofluorescence staining in HepG2 and human intestinal smooth muscle cell lines. In human tissue sections, TRIM37 shows a granular cytoplasmic pattern. Endogenous TRIM37 is not imported into peroxisomes in peroxin 1 (PEX1(-/-)) and peroxin 5 (PEX5(-/-)) mutant fibroblasts but is imported normally in peroxin 7 (PEX7(-/-)) deficient fibroblasts, giving further evidence for a peroxisomal localization of TRIM37. Fibroblasts derived from patients with mulibrey nanism lack C-terminal TRIM37 immunoreactivity but stain normally for both peroxisomal matrix and membrane markers, suggesting apparently normal peroxisome biogenesis in patient fibroblasts. Taken together, this molecular evidence unequivocally indicates that TRIM37 is located in the peroxisomes, and Mulibrey nanism thus can be classified as a new peroxisomal disorder.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2002

AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.3. This monogenic disease provides an interesting model for studies of other common and more complex autoimmune diseases. The most common components of APECED are chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, but several other endocrine deficiencies and ectodermal dystrophies also occur and the phenotype varies widely. The AIRE genotype also varies; 42 different mutations have been reported so far. To understand the complexity of the phenotype, we studied the AIRE and human leukocyte antigen (HLA) class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, R257X, than in those with other mutations. Addison's disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04- DQB1*0302 (P < 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15-DQB1*0602 (P = 0.036). The same HLA associations have previously been established for non-APECED patients. We conclude that mutation of AIRE per se has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant.

Adolescent↗