Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins

H. S. Scott, M. Heino, P. Peterson, L. Mittaz, M. D. Lalioti, C. Betterle, A. Cohen, M. Seri, M. Lerone, G. Romeo, P. Collin, M. Salo, R. Metcalfe, A. Weetman, M. P. Papasavvas, C. Rossier, K. Nagamine, Jun Kudo, N. Shimizu, K. J E Krohn & 1 others S. E. Antonarakis

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1112-1119
Number of pages8
JournalMolecular Endocrinology
Volume12
Issue number8
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

Autoimmune Polyendocrinopathies
Mutation
Alleles
Haplotypes
Autoimmune Diseases
Chronic Mucocutaneous Candidiasis
Genetic Databases
Addison Disease
Hypoparathyroidism
Amino Acid Motifs
Endocrine System
Zinc Fingers
Thyroid Diseases
Gastritis
Amino Acid Substitution
Type 1 Autoimmune polyendocrinopathy syndrome
Type 1 Diabetes Mellitus
Proline
Thymus Gland
Fingers

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Scott, H. S., Heino, M., Peterson, P., Mittaz, L., Lalioti, M. D., Betterle, C., ... Antonarakis, S. E. (1998). Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Molecular Endocrinology, 12(8), 1112-1119.

Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. / Scott, H. S.; Heino, M.; Peterson, P.; Mittaz, L.; Lalioti, M. D.; Betterle, C.; Cohen, A.; Seri, M.; Lerone, M.; Romeo, G.; Collin, P.; Salo, M.; Metcalfe, R.; Weetman, A.; Papasavvas, M. P.; Rossier, C.; Nagamine, K.; Kudo, Jun; Shimizu, N.; Krohn, K. J E; Antonarakis, S. E.

In: Molecular Endocrinology, Vol. 12, No. 8, 1998, p. 1112-1119.

Research output: Contribution to journalArticle

Scott, HS, Heino, M, Peterson, P, Mittaz, L, Lalioti, MD, Betterle, C, Cohen, A, Seri, M, Lerone, M, Romeo, G, Collin, P, Salo, M, Metcalfe, R, Weetman, A, Papasavvas, MP, Rossier, C, Nagamine, K, Kudo, J, Shimizu, N, Krohn, KJE & Antonarakis, SE 1998, 'Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins', Molecular Endocrinology, vol. 12, no. 8, pp. 1112-1119.
Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C et al. Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Molecular Endocrinology. 1998;12(8):1112-1119.
Scott, H. S. ; Heino, M. ; Peterson, P. ; Mittaz, L. ; Lalioti, M. D. ; Betterle, C. ; Cohen, A. ; Seri, M. ; Lerone, M. ; Romeo, G. ; Collin, P. ; Salo, M. ; Metcalfe, R. ; Weetman, A. ; Papasavvas, M. P. ; Rossier, C. ; Nagamine, K. ; Kudo, Jun ; Shimizu, N. ; Krohn, K. J E ; Antonarakis, S. E. / Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. In: Molecular Endocrinology. 1998 ; Vol. 12, No. 8. pp. 1112-1119.
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abstract = "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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AU - Peterson, P.

AU - Mittaz, L.

AU - Lalioti, M. D.

AU - Betterle, C.

AU - Cohen, A.

AU - Seri, M.

AU - Lerone, M.

AU - Romeo, G.

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AU - Salo, M.

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AU - Rossier, C.

AU - Nagamine, K.

AU - Kudo, Jun

AU - Shimizu, N.

AU - Krohn, K. J E

AU - Antonarakis, S. E.

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