A Novel Missense Mutation of AIRE Gene in a Patient with Autoimmune Polyendocrinopathy, Candidiasis and Ectodermal Dystrophy (APECED), Accompanied with Progressive Muscular Atrophy: Case Report and Review of the Literature in Japan.

Abstract

Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

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

“…However, possible subclinical indications, e.g., the presence of different autoantibodies, have not been studied. There is also a growing number of other studies reporting heterozygous carriers of the AIRE mutations being clinically or subclinically affected [Cihakova et al, 2001;Sato et al, 2002;Sediva et al, 2002;Buzi et al, 2003]. Several mutations (missense, nonsense, and deletion) are represented among these cases.…”

“…Additionally, the mutation appears to carry an unusually high risk for hypothyroid autoimmune thyroiditis (hAT) [Cetani et al, 2001]. Further, increasing numbers of studies report heterozygotes that are clinically or subclinically affected [Cihakova et al, 2001;Sato et al, 2002;Sediva et al, 2002;Buzi et al, 2003].…”

Polyglandular autoimmune syndromes

“…In populations with rather low genetic diversity, higher prevalence has been described, e.g., Iranian Jews (1:9000), Sardinians (1:14,000) or Finns (1:25,000). The prevalence of PAS I is lower in Japanese populations (1:10,000,000) [20][21][22][23]. The female/male ratio of PAS I is 0.8-2.4 showing a slight female predominance [7,24].…”

Immunoregulatory and Susceptibility Genes in Thyroid and Polyglandular Autoimmunity

“…It contains zinc finger motifs and is thought to have transcriptional regulatory activity suggestive of a transcription factor (93); but the mechanisms regulating AIRE gene expression are not known. In the coding region of the AIRE gene, more than 45 mutations have been reported including nonsense and missense mutations, deletions, and insertions (94)(95)(96)(97)(98). Most frequently observed mutations in European and North American populations are the mutation R257X in exon 6 (C/T transition) and the 13 bp deletion in exon 8 (99).…”