A Novel AIRE Mutation in an APECED Patient with Candidiasis, Adrenal Failure, Hepatitis, Diabetes Mellitus and Osteosclerosis

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, which is characterized by an immune-mediated destruction of endocrine tissues, chronic candidiasis and ectodermal disorders. In contrast to many other autoimmune diseases, APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe an APECED patient with severe deformities of the tibia with radiological signs of metaphyseal dysplasia in addition to candidiasis, hepatitis, diabetes mellitus and adrenal failure. In this patient, we identified a novel AIRE mutation in association with the C322fsX372 mutation in exon 8, which is frequently detected in Caucasian patients. The frame shift mutation G263fsX377 in exon 6 results in a protein lacking both PHD zinc-finger domains similar to the R257 X mutation. This novel mutation was not found in 50 German controls.

AIRE - APECED - mutations - autoimmunity - osteosclerosis

References

• 1 Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.  N Engl J Med. 1990;  322 1829-1836
• 2 Betterle C, Greggio N A, Volpato M. Autoimmune polyglandular syndrome type 1. J. Clin.  Endocrinol Metab. 1998;  83 1049-1055
• 3 Bjorses P, Halonen M, Palvimo J J, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.  Am J Hum Genet. 2000;  66 378-392
• 4 Consortium. TF-GA: An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. The Finnish-German APECED Consortium. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy.  Nat Genet. 1997;  17 399-403
• 5 Halonen M, Eskelin P, Myhre A G. et al . AIRE Mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.  J Clin Endocrinol Metab. 2002;  87 2568-2574
• 6 Ishii T, Suzuki Y, Ando N, Matsuo N, Ogata T. Novel mutations of the autoimmune regulator gene in two siblings with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.  J Clin Endocrinol Metab. 2000;  85 2922-2926
• 7 Kumar P G, Laloraya M, Wang C Y, Ruan Q G, Davoodi-Semiromi A, Kao K J, She J X. The autoimmune regulator (AIRE) is a DNA-binding protein.  J Biol Chem. 2001;  276 41357-41364
• 8 Meloni A, Perniola R, Faa V, Corvaglia E, Cao A, Rosatelli M C. Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.  J Clin Endocrinol Metab. 2002;  87 841-846
• 9 Nagamine K, Peterson P, Scott H S, Kudoh J, Minoshima S, Heino M, Krohn K J, Lalioti M D, Mullis P E, Antonarakis S E, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene.  Nat Genet. 1997;  17 393-398
• 10 Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kampe O, Eskelin P, Pelto-Huikko M, Peltonen L. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response.  Hum Mol Genet. 2002;  11 397-409
• 11 Vogel A, Liermann H, Harms A, Strassburg C P, Manns M P, Obermayer-Straub P. Autoimmune regulator AIRE: Evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1.  Hepatology. 2001;  33 1047-1052
• 12 Vogel A, Strassburg C P, Obermayer-Straub P, Brabant G, Manns M P. The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components.  J Mol Med. 2002;  80 201-210
• 13 Zlotogora J, Shapiro M S. Polyglandular autoimmune syndrome type I among Iranian Jews.  J Med Genet. 1992;  20 824-826