A Common and Recurrent 13-bp Deletion in the Autoimmune Regulator Gene in British Kindreds with Autoimmune Polyendocrinopathy Type 1

Abstract

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.

Polyglandular autoimmune syndromes

“…PAS I is a monogenic disease with autosomal recessive inheritance (52)(53)(54)(55)(56)(57)(58)(59)(60). Mutations of a single gene termed the autoimmune regulator (AIRE) gene play a crucial role.…”

Genetic control of autoimmunity in Type I diabetes and associated disorders

“…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.…”

Erythropoietin‐deficient anemia associated with autoimmune polyglandular syndrome type I

“…Mutations of the AIRE gene (autoimmune regulator), located at 21q22.3, are responsible for the syndrome [4]. At least 45 disease-causing mutations have been identified, the most common of which is the R257X mutation, reported in 89% of Finnish and 33% of non-Finnish cases [5].…”

“…At least 45 disease-causing mutations have been identified, the most common of which is the R257X mutation, reported in 89% of Finnish and 33% of non-Finnish cases [5]. In addition, a 13-bp deletion (964del13) accounts for many cases of APS1 in Great Britain, and a common haplotype spanning the AIRE-1 locus in chromosomes carrying the 964del13 mutation has suggested a founder effect in this population [4]. AIRE was recently described as a 13-kb gene with 14 exons encoding a 545-amino acid protein [6].…”

“…In addition to typical features of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis, patients with APECED can also develop type I diabetes mellitus, gonadal failure, thyroid dysfunction, panhypopituitarism, autoimmune hepatitis, asplenism, gastric atrophy, malabsorbtion, squamous cell carcinoma of the oral mucosa, and pernicious anemia [4,11,12]. Pernicious anemia is seen in up to 16% of APECED patients, but other forms of anemia have been occasionally noted as well [13].…”