Elizaveta M Orlova1,2, Leila S Sozaeva1, Maria A Kareva1, Bergithe E Oftedal3, Anette S B Wolff3, Lars Breivik3, Ekaterina Y Zakharova1,4, Olga N Ivanova1, Olle Kämpe5, Ivan I Dedov1, Per M Knappskog6, Valentina A Peterkova1,2, Eystein S Husebye3,5,7. 1. Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia. 2. I. M. Sechenov First Moscow State Medical University, Moscow 117036, Russia. 3. Department of Clinical Science, University of Bergen, Bergen 5020, Norway. 4. Research Centre for Medical Genetics, Laboratory of Metabolic Disorders, Moscow 115478, Russia. 5. Department of Medicine, Solna, Karolinska Institutet, Stockholm 17177, Sweden. 6. Center for Medical Genetics and Molecular Medicine, Haukeland University and Hospital, Bergen 5021, Norway. 7. Department of Medicine, Haukeland University and Hospital, Bergen 5021, Norway.
Abstract
Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
Context:Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
Authors: Elise M N Ferré; Timothy J Break; Peter D Burbelo; Michael Allgäuer; David E Kleiner; Dakai Jin; Ziyue Xu; Les R Folio; Daniel J Mollura; Muthulekha Swamydas; Wenjuan Gu; Sally Hunsberger; Chyi-Chia R Lee; Anamaria Bondici; Kevin W Hoffman; Jean K Lim; Kerry Dobbs; Julie E Niemela; Thomas A Fleisher; Amy P Hsu; Laquita N Snow; Dirk N Darnell; Samar Ojaimi; Megan A Cooper; Martin Bozzola; Gary I Kleiner; Juan C Martinez; Robin R Deterding; Douglas B Kuhns; Theo Heller; Karen K Winer; Arun Rajan; Steven M Holland; Luigi D Notarangelo; Kevin P Fennelly; Kenneth N Olivier; Michail S Lionakis Journal: Sci Transl Med Date: 2019-06-05 Impact factor: 17.956
Authors: Monica M Schmitt; Elise M N Ferré; Michelly Sampaio De Melo; Megan A Cooper; Martha M Quezado; Theo Heller; Michail S Lionakis Journal: JPGN Rep Date: 2021-11