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Common Mutations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients of Different Origins

Laboratory of Human Molecular Genetics (H.S.S., L.M., M.D.L., M-P.P., C.R., S.E.A.) Department of Genetics and Microbiology University of Geneva Medical School and Division of Medical Genetics (S.E.A.) Cantonal Hospital of Geneva 1211 Geneva 4, Switzerland
Institute of Medical Technology and University Hospital (M.H., P.P., P.C., M.S., K.J.E.K.) University of Tampere 33101 Tampere, Finland
Institute of Semeiotica Medica (C.B.) University of Padova 35128 Padova, Italy
Pediatric Endocrinology Unit (A.C.) Laboratorio di Genetica Molecolare (M.S., M.L.) Istituto G. Gaslini University of Genova Medical School (G.R.) Genova, I-16148, Italy
Division of Clinical Sciences (R.M., A.W.) Northern General Hospital University of Sheffield Sheffield SS 7AU, United Kingdom
Department of Molecular Biology (K.N., J.K., N.S.) Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo 160, Japan

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM *240300, also called APS 1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is generally characterized by two of the three major clinical symptoms that may be present, Addison’s disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have a number of other clinical symptoms including chronic gastritis, gonadal failure, and rarely, autoimmune thyroid disease and insulin-dependent diabetes mellitus. We and others have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes, and fetal liver and encodes a protein containing motifs suggestive of a transcriptional regulator, including two zinc finger motifs (PHD finger), a proline-rich region, and three LXXLL motifs. Six mutations, including R257X, the predominant Finnish APECED allele, have been defined. R257X was also observed in non-Finnish APECED patients occurring on different chromosomal haplotypes suggesting different mutational origins. Here we present mutation analyses in an extended series of patients, mainly of Northern Italian origin. We have detected 12 polymorphisms, including one amino acid substitution, and two additional mutations, R203X and X546C, in addition to the previously described mutations, R257X, 1096–1097insCCTG, and a 13-bp deletion (1094–1106del). R257X was also the common mutation in the Northern Italian patients (10 of 18 alleles), and 1094–1106del accounted for 5 of 18 Northern Italian alleles. Both R257X and 1094–1106del were both observed in patients of four different geo-ethnic origins, and both were associated with multiple different haplotypes using closely flanking polymorphic markers showing likely multiple mutation events (six and four, respectively). The identification of common AIRE mutations in different APECED patient groups will facilitate its genetic diagnosis. In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system.

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