title: 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.
authors.affiliation: Department of Medicine, The Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom. spearce@hgmp.mrc.ac.uk
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
authors.forename: T
authors.initials: T
authors.lastname: Cheetham
authors.forename: H
authors.initials: H
authors.lastname: Imrie
authors.forename: B
authors.initials: B
authors.lastname: Vaidya
authors.forename: N D
authors.initials: ND
authors.lastname: Barnes
authors.forename: R W
authors.initials: RW
authors.lastname: Bilous
authors.forename: D
authors.initials: D
authors.lastname: Carr
authors.forename: K
authors.initials: K
authors.lastname: Meeran
authors.forename: N J
authors.initials: NJ
authors.lastname: Shaw
authors.forename: C S
authors.initials: CS
authors.lastname: Smith
authors.forename: A D
authors.initials: AD
authors.lastname: Toft
authors.forename: G
authors.initials: G
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Kendall-Taylor
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009679:Nuclear Family; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D000096927:AIRE Protein