Common Mutations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients of Different Origins

Scott, Hamish S.; Heino, Maarit; Peterson, Pärt; Mittaz, Lauréane; Lalioti, Maria D.; Betterle, Corrado; Cohen, Amnon; Seri, Marco; Lerone, Margherita; Romeo, Giovanni; Collin, Pekka; Salo, Matti K.; Metcalfe, Russell; Weetman, Anthony P.; Papasavvas, Marie-Pierre; Rossier, Colette; Nagamine, Kentaro; Kudoh, Jun; Shimizu, Nobuyoshi; Krohn, Kai; Antonarakis, Stylianos E.

doi:10.1210/mend.12.8.0143

Cited by 127 publications

(94 citation statements)

References 23 publications

(28 reference statements)

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“…Over 31 different mutations in the AIRE-1 gene have been described. The most frequent mutations are a 13-bp deletion in exon 8 (1085±1097 del) among Norwegian patients [142]; a Arg257Stop mutation among Finnish; R139X in Sardinia [143]; R257X in Northern Italy; 1096±1097insCCTG, 1094±1106del, R203X and X546C [150]; 1094±1106del and R257 in an ethnically mixed population in North America [151]; a 13-bp deletion (964del13) mutation in Britain [152]; a missense mutation (Pro326Leu) in a large French family [153]. To date, no correlation has been found between specific mutations and variation in clinical phenotype.…”

Section: ªMonogenicº Diabetes Syndromesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Section: ªMonogenicº Diabetes Syndromesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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“…Post mortem sequencing of the AIRE gene was performed as described by SCOTT et al [16] and revealed homozygous substitution of cytosine by thymine in nucleotide position 8473.…”

Section: Case Reportmentioning

confidence: 99%

Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome

Korniszewski

Kurzyna²,

Stolarski³

et al. 2003

Eur Respir J

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the autoimmune regulator (AIRE) gene, which has a central function in maintaining immunological tolerance. A number of conditions with proven or likely autoimmune pathogenesis occur in APECED: hypoparathyroidism, adrenocortical insufficency, candidiasis, hypogonadism, type 1 diabetes, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy. It is not clear which factors are responsible for variation in clinical picture of APECED, but human leukocyte antigen (HLA) genotype may be important.The authors report the first description of a case of primary pulmonary hypertension (PPH) in patient with APECED, caused by R257X mutation in AIRE. The HLA genotype of the patient (DRB1*01/DRB1*11, DQB1*0301/DQB1*0501) has been previously reported as a predisposing factor to PPH.The findings from this study, provided that other similar cases are reported, suggest that immune deregulation plays a role in the pathogenesis of primary pulmonary hypertension. Autoimmune polyglandular syndrome type I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM 240300), is an autosomal recessive disorder caused by mutations causing loss of function of the autoimmune regulator (AIRE) protein [1]. The AIRE protein is a transcriptional regulator expressed mainly in the thymus and plays a central role in the development and maintenance of immunological tolerance by promoting the ectopic expression of peripheral tissue-restricted antigens in medullary epithelial cells of the thymus [2]. The lack of AIRE results in a number of manifestations with proven or likely autoimmune pathogenesis, of which the most common are hypoparathyroidism, primary adrenocortical insufficency and candidiasis, whereas hypogonadism, insulin-dependent diabetes mellitus, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy, occur less frequently [3]. It is not clear which factors are responsible for the variation in the clinical picture of APECED. The human leukocyte antigen (HLA) genotype may be important, since it was observed that autoimmune conditions in the APECED cohort showed HLA associations that were similar to those found in non-APECED patients with respective autoimmune disorders [4].Primary pulmonary hypertension (PPH) is a disorder characterised by lesions of pulmonary arterioles, which increase vascular resistance and lead to elevated pulmonary arterial pressure. The pathogenesis of PPH is not clear but recently it has been put in a novel perspective by the demonstration of mutations in BMPR-II (bone morphogenic protein receptor II) in a proportion of patients [5][6][7]. BMPR-II is a ubiquitously expressed receptor for a group of growth factors belonging to the transforming growth factor beta superfamily [7,8]. Conversely, since the majority of mutations in BMPR-II were found in familial cases of PPH, it is not cl...

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“…29,33,35 The other frequently occurring mutation, 967-979del13bp, is the most common mutation in Anglo-American APECED patients, accounting for 70% of British and 53% of North American APECED alleles studied, as well as having been reported in several APECED cases from other populations. 27,28,32 A large proportion of the AIRE mutations are stop mutations usually resulting in a truncated protein lacking the second or both PHD fingers.…”

Section: Mutations In the Aire Genementioning

confidence: 98%

“…So far 46 different APECED causing mutations have been identified in the AIRE gene [10][11][12][13][14][15][16][17][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] ( Figure 1). The mutations are found throughout the coding region of the AIRE gene though clearly two mutation hotspots arise.…”

Section: Mutations In the Aire Genementioning

confidence: 99%

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Autoimmune regulator: from loss of function to autoimmunity

2003

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The autoimmune regulator (AIRE) is a gene where mutations cause the recessively inherited disorder called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autoimmune polyendocrinopathy syndrome type 1 (APS1). Variable combinations of autoimmune endocrine diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes characterize APECED. The AIRE protein has several domains indicative of a transcriptional regulator. AIRE contains two PHD (plant homeodomain) type zinc fingers, four nuclear receptor binding LXXLL motifs, a putative DNA-binding domain named SAND and, in addition, a highly conserved N-terminal domain similar to the homogenously staining region domain of the Sp100 protein. At the subcellular level, AIRE is expressed in nuclear dots resembling promyelocytic leukemia nuclear bodies, which are associated with several transcriptionally active proteins. AIRE is primarily expressed in thymic medullary epithelial cells and monocyte-dendritic cells in the thymus but also in a rare subset of cells in the lymph nodes, spleen and fetal liver. The disease, caused by mutations in AIRE, its function as a protein involved in transcription, and its restricted expression in cells important in negative selection, all together suggest that AIRE is a central protein in the maintenance of immune tolerance. In this review of the recent literature we discuss the results of these studies with particular attention on the AIRE expression pattern and its function as a transcriptional regulator, as well as the effects of patient mutations on the molecular characteristics of the protein.

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Common Mutations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients of Different Origins

Cited by 127 publications

References 23 publications

Genetic control of autoimmunity in Type I diabetes and associated disorders

Genetic control of autoimmunity in Type I diabetes and associated disorders

Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome

Autoimmune regulator: from loss of function to autoimmunity

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