Oxford Genetics Laboratories, Churchill Hospital, Oxford, UK.
Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Eur J Endocrinol. 2022 May 24;187(1):111-122. doi: 10.1530/EJE-21-0730.
The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.
Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.
Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.
This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.
自身免疫性多内分泌腺综合征 1 型（APS-1）是一种常染色体隐性疾病，其特征为免疫失调和自身免疫性内分泌腺破坏。APS-1 是由影响染色体 21q22.3 上自身免疫调节因子（AIRE）基因的双等位基因突变引起的，该基因有助于免疫耐受。本研究旨在调查 300 多名疑似 APS-1 或孤立性甲状旁腺功能减退症的患者的 AIRE 异常。
通过 DNA 序列分析对先证者进行评估。使用 AIRE 蛋白的 3D 建模来描述新的变异。使用限制性内切酶和微卫星分析来研究单亲二体性。
在 35 名 APS-1 患者和 5 名孤立性甲状旁腺功能减退症患者中发现了双等位基因 AIRE 突变。其中包括一种新型纯合 p.(His14Pro)突变，预计会破坏 AIRE 蛋白的 N 端半胱氨酸蛋白酶激活募集结构域。此外，在一名 APS-1 患者中发现了一种明显的纯合 AIRE 突变 p.Leu323fs，该患者是无血缘关系的无症状父母的孩子。微卫星分析显示，该患者由于单亲二体性而继承了两个父系突变 AIRE 等位基因。甲状旁腺功能减退症是 AIRE 突变阳性先证者中最常见的内分泌表现，>45%的携带 AIRE 突变的患者至少有三联症中的两种疾病，即念珠菌病、甲状旁腺功能减退症和肾上腺功能减退症。相比之下，在疑似 APS-1 的 AIRE 突变阴性先证者中，1 型糖尿病和甲状腺功能减退症更为常见。在孤立性甲状旁腺功能减退症的 AIRE 突变阴性先证者中，约有 30%的人携带其他甲状旁腺功能减退症基因的突变。
本研究对一个大的候选人群进行了 AIRE 突变分析，扩展了导致 APS-1 的遗传异常谱。
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