Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder that results in several autoimmune diseases due to the mutations in the AIRE (autoimmune regulator) gene. APECED patients develop several autoimmune endocrine disorders and are characterized by the high titer autoantibodies to organ-specific antigens such as the steroidogenic P450 cytochromes. So far, 38 mutations have been identified in the AIRE gene. We report here the genetic and autoantibody analysis of 27 APECED patients of Eastern and Central European origins and one Egyptian patient. From 54 analyzed APECED chromosomes, eight mutations were detected, four of which (T16M, W78R, IVS1_IVS4, 30-53dup23bp) are novel. The most prevalent reason for APECED in these populations was the occurrence of R257X (36 chromosomes) that has been described earlier as a common and recurrent mutation in several other populations. The analysis of humoral immunity to steroidogenic P450 cytochromes by the immunoblotting of E. coli expressed antigens in the 18 APECED patients showed that 67%, 44%, and 61% of the Eastern and Central European APECED patients had autoantibodies to P450c17, P450c21, and P450scc, respectively.

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I

“…Standard mutational screening techniques with PCR-amplification followed by sequencing of the amplified product fail to detect the number of copies of the specified region. On the webpage for 'Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff' http://www.hgmd.cf.ac.uk/ac/all.php only two big deletions of AIRE are listed (IVS1_IVS4, 1734 bp intron 1-exon 4 28 and c.191_226del36 in exon 2 29 ). The deletions reported here are the largest deletions that have been reported in this gene.…”

Autoimmune regulator: from loss of function to autoimmunity

“…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.…”

“…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.…”

“…9,33 Similar to these data, candidiasis has not been diagnosed in Finnish patients with a K83E mutation 12 and in Czech patients with a W78R mutation. 35 At least one mutation (G228W), acting in a dominant fashion and cosegregating with hypothyroid autoimmune thyroiditis, has been described in an Italian APECED kindred. 39 The other genetic or environmental factors behind the APECED variation remain unknown.…”

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) due to AIRET16M mutation in a consanguineous Greek girl

“…Autoimmune polyendocrinopathy-candidiasis-ectodermal dystro phy syndrome (APECED) or autoimmune polyen docrine syndrome type 1 (APS-1) is a rare autosomal recessive disease (1 -3) generally seen in infants and children that is caused by mutations of the AutoImmune REgulator ( AIRE ) gene on chromosome 21q22.3 (4,5) . It is characterized by the presence of at least two of three components: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison ' s disease, but can also include other clinical manifestations, such as autoimmune thyroid disease, type 1 diabetes mellitus, alopecia, vitiligo, ectodermal dystrophy, malabsorption and pernicious anemia (6) .…”