A novel variant in AIRE causing a rare, non‑classical autoimmune polyendocrine syndrome type 1

Zheng,Wen‑Bin; Li,Lu‑Jiao; Zhao,Di‑Chen; Wang,Ou; Jiang,Yan; Xia,Wei‑Bo; Li,Mei

doi:10.3892/mmr.2020.11227

A novel variant in AIRE causing a rare, non‑classical autoimmune polyendocrine syndrome type 1

Authors:
- Wen‑Bin Zheng
- Lu‑Jiao Li
- Di‑Chen Zhao
- Ou Wang
- Yan Jiang
- Wei‑Bo Xia
- Mei Li
View Affiliations

Affiliations: Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
Published online on: June 12, 2020 https://doi.org/10.3892/mmr.2020.11227
Pages: 1285-1294
Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Autoimmune polyendocrine syndrome type 1 (APS‑1) is a rare inherited autoimmune disease, characterized by a classic triad, including chronic mucocutaneous candidiasis, primary adrenocortical insufficiency and hypoparathyroidism. The present study investigated phenotypes and pathogenic variants in a Chinese woman with non‑classical APS‑1. Disease‑associated variants in a patient with APS‑1 were identified via targeted next generation sequencing and the variant was confirmed via Sanger sequencing. Serum levels of calcium, phosphorus, parathyroid hormone (PTH), follicle‑stimulating hormone (FSH), luteinizing hormone (LH), estradiol and urinary levels of calcium were measured. Blood count assays and bone marrow morphology were investigated. The patient was a 32‑year‑old woman who had suffered from typical carpopedal spasms since she was 7 years old. She developed syncope, primary amenorrhea, intermittent diarrhea and general fatigue in subsequent years. Hypocalcemia, hyperphosphatemia, low levels of PTH and estradiol, elevated levels of FSH and LH, and absence of erythroblasts were observed, which indicated hypoparathyroidism, primary ovarian insufficiency and pure red cell aplasia. A novel heterozygous missense variant (NM_000383.2: c.623G>T, NP_000374.1: p.Gly208Val) in exon 5 of autoimmune regulator and a reported variant (NM_000383.2: c.371C>T, NP_000374.1: p.Pro124Leu) in exon 3 were detected, of which the c.623G>T variant may be a pathogenic variation that induces APS‑1. Under a regular follow‑up and therapeutic adjustment of calcium, calcitriol, hormone replacement therapy and methylprednisolone, the endocrine function and clinical symptoms of the patient were notably improved. The results of the present study expand the known genetic and phenotypical spectra of APS‑1.

View Figures

View References

1	Sepe V, Velluzzi F and Songini M: Autoimmune polyendocrine syndromes. N Engl J Med. 378:25432018.PubMed/NCBI
2	Husebye ES, Anderson MS and Kämpe O: Autoimmune polyendocrine syndromes. N Engl J Med. 378:1132–1141. 2018. View Article : Google Scholar : PubMed/NCBI
3	Bruserud Ø, Oftedal BE, Landegren N, Erichsen MM, Bratland E, Lima K, Jørgensen AP, Myhre AG, Svartberg J, Fougner KJ, et al: A longitudinal follow-up of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 101:2975–2983. 2016. View Article : Google Scholar : PubMed/NCBI
4	Orlova EM, Sozaeva LS, Kareva MA, Oftedal BE, Wolff ASB, Breivik L, Zakharova EY, Ivanova ON, Kämpe O, Dedov II, et al: Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 102:3546–3556. 2017. View Article : Google Scholar : PubMed/NCBI
5	Gutierrez MJ, Gilson J, Zacharias J, Ishmael F and Bingham CA: Childhood polyarthritis as early manifestation of autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy syndrome. Front Immunol. 8:3772017. View Article : Google Scholar : PubMed/NCBI
6	Bruserud Ø, Oftedal BE, Wolff AB and Husebye ES: AIRE-mutations and autoimmune disease. Curr Opin Immunol. 43:8–15. 2016. View Article : Google Scholar : PubMed/NCBI
7	Zhu W, Hu Z, Liao X, Chen X, Huang W, Zhong Y and Zeng Z: A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1. Immunogenetics. 69:643–651. 2017. View Article : Google Scholar : PubMed/NCBI
8	Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, et al: Positional cloning of the APECED gene. Nat Genet. 17:393–398. 1997. View Article : Google Scholar : PubMed/NCBI
9	Zhao B, Chang L, Fu H, Sun G and Yang W: The role of autoimmune regulator (AIRE) in peripheral tolerance. J Immunol Res. 2018:39307502018. View Article : Google Scholar : PubMed/NCBI
10	Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, Furcas M, Rosatelli MC, Cao A and Congia M: Autoimmune polyendocrine syndrome type 1: An extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 97:1114–1124. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zlotogora J and Shapiro MS: Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. 29:824–826. 1992. View Article : Google Scholar : PubMed/NCBI
12	Rosatelli MC, Meloni A, Meloni A, Devoto M, Cao A, Scott HS, Peterson P, Heino M, Krohn KJ, Nagamine K, et al: A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum Genet. 103:428–434. 1998. View Article : Google Scholar : PubMed/NCBI
13	Liu Y, Asan, Ma D, Lv F, Xu X, Wang J, Xia W, Jiang Y, Wang O, Xing X, et al: Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. Osteoporos Int. 28:2985–2995. 2017. View Article : Google Scholar : PubMed/NCBI
14	Liu C, Shi Y, Yin H, Li H, Fan S, Wu S and Yuan P: Autoimmune regulator gene mutations in a Chinese family with autoimmune polyendocrinopathy syndrome type I. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 27:18–22. 2010.(In Chinese). PubMed/NCBI
15	Zhang J, Liu H, Liu Z, Liao Y, Guo L, Wang H, He L, Zhang X and Xing Q: A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1. PLoS One. 8:e539812013. View Article : Google Scholar : PubMed/NCBI
16	Jin P, Zhang Q, Dong CS, Zhao SL and Mo ZH: A novel mutation in autoimmune regulator gene causes autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Endocrinol Invest. 37:941–948. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sun YX, He YF and Li XL: Clinical analysis and autoimmune regulator gene mutation of autoimmune polyendocrinopathy syndrome type I in a family: A report of one case. Zhongguo Dang Dai Er Ke Za Zhi. 18:147–151. 2016.(In Chinese). PubMed/NCBI
18	Oftedal BE, Hellesen A, Erichsen MM, Bratland E, Vardi A, Perheentupa J, Kemp EH, Fiskerstrand T, Viken MK, Weetman AP, et al: Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity. 42:1185–1196. 2015. View Article : Google Scholar : PubMed/NCBI
19	Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A and Marcocci C: A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab. 86:4747–4752. 2001. View Article : Google Scholar : PubMed/NCBI
20	Ilmarinen T, Eskelin P, Halonen M, Ruppell T, Kilpikari R, Torres GD, Kangas H and Ulmanen I: Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Hum Mutat. 26:322–331. 2005. View Article : Google Scholar : PubMed/NCBI
21	Su MA, Giang K, Zumer K, Jiang H, Oven I, Rinn JL, Devoss JJ, Johannes KP, Lu W, Gardner J, et al: Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J Clin Invest. 118:1712–1726. 2008. View Article : Google Scholar : PubMed/NCBI
22	Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C and Mathis D: Projection of an immunological self shadow within the thymus by the aire protein. Science. 298:1395–1401. 2002. View Article : Google Scholar : PubMed/NCBI
23	Kisand K and Peterson P: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: Known and novel aspects of the syndrome. Ann N Y Acad Sci. 1246:77–91. 2011. View Article : Google Scholar : PubMed/NCBI
24	Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I and 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. 66:378–392. 2000. View Article : Google Scholar : PubMed/NCBI
25	Johnnidis JB, Venanzi ES, Taxman DJ, Ting JP, Benoist CO and Mathis DJ: Chromosomal clustering of genes controlled by the aire transcription factor. Proc Natl Acad Sci USA. 102:7233–7238. 2005. View Article : Google Scholar : PubMed/NCBI
26	Peterson P, Org T and Rebane A: Transcriptional regulation by AIRE: Molecular mechanisms of central tolerance. Nat Rev Immunol. 8:948–957. 2008. View Article : Google Scholar : PubMed/NCBI
27	Ramsey C, Bukrinsky A and Peltonen L: Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. Hum Mol Genet. 11:3299–3308. 2002. View Article : Google Scholar : PubMed/NCBI
28	Ilmarinen T, Melen K, Kangas H, Julkunen I, Ulmanen I and Eskelin P: The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin alpha molecules. FEBS J. 273:315–324. 2006. View Article : Google Scholar : PubMed/NCBI
29	Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, et al: Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 358:1018–1028. 2008. View Article : Google Scholar : PubMed/NCBI
30	Habibullah M, Porter JA, Kluger N, Ranki A, Krohn KJE, Brandi ML, Brown EM, Weetman AP and Kemp EH: Calcium-sensing receptor autoantibodies in patients with autoimmune polyendocrine syndrome type 1: Epitopes, specificity, functional affinity, IgG subclass, and effects on receptor activity. J Immunol. 201:3175–3183. 2018. View Article : Google Scholar : PubMed/NCBI
31	Meloni A, Perniola R, Faà V, Corvaglia E, Cao A and Rosatelli MC: Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. J Clin Endocrinol Metab. 87:841–846. 2002. View Article : Google Scholar : PubMed/NCBI
32	Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, Will H, Vähämurto P, Ollila J, Scott HS, et al: The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J Biol Chem. 275:16802–16809. 2000. View Article : Google Scholar : PubMed/NCBI
33	Cihakova D, Trebusak K, Heino M, Fadeyev V, Tiulpakov A, Battelino T, Tar A, Halasz Z, Blümel P, Tawfik S, et al: Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED. Hum Mutat. 18:225–232. 2001. View Article : Google Scholar : PubMed/NCBI
34	Bøe Wolff AS, Oftedal B, Johansson S, Bruland O, Lovas K, Meager A, Pedersen C, Husebye ES and Knappskog PM: AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): Partial gene deletions contribute to APS I. Genes Immun. 9:130–136. 2008. View Article : Google Scholar : PubMed/NCBI
35	Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, Fougner KJ, Lima K, Knappskog PM and Husebye ES: Autoimmune polyendocrine syndrome type 1 in Norway: Phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 92:595–603. 2007. View Article : Google Scholar : PubMed/NCBI
36	Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 91:2843–2850. 2006. View Article : Google Scholar : PubMed/NCBI
37	Ahonen P, Myllärniemi S, Sipilä I and Perheentupa J: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 322:1829–1836. 1990. View Article : Google Scholar : PubMed/NCBI
38	Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, Thakker RV, Khan AA and Potts JT Jr: Management of hypoparathyroidism: Summary statement and guidelines. J Clin Endocrinol Metab. 101:2273–2283. 2016. View Article : Google Scholar : PubMed/NCBI
39	Means RT Jr: Pure red cell aplasia. Blood. 128:2504–2509. 2016. View Article : Google Scholar : PubMed/NCBI