Mutations In Autoimmune Regulator Gene Research Articles

Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants

ObjectiveAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000–200,000 worldwide and 1/6500–9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families.MethodsWe sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents.ResultsIn total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison’s disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents.ConclusionHere, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

BackgroundAutoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD).MethodsAutoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined.ResultsThe prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases.ConclusionsIn Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study.

ObjectiveAutoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.DesignTwenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years.MethodsClinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.ResultsPatients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.ConclusionsIndian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

AIRE Gene Mutation in Chinese APS-1 Patients

Autoimmune polyendocrine syndrome type 1 (APS-1, OMIM 2403000) is a rare autosomal recessive disease that is caused by autoimmune regulator (AIRE) gene. The main symptoms of APS-1 are chronic mucocutaneous candidiasis, autoimmune adrenocortical insufficiency (Addison’s disease) and hypoparathyroidism. To date, more than 100 different mutations of the AIRE gene have been identified in APS-1 patients. These different mutations affect the structure and function of the AIRE protein in different ways, which eventually leads to the development of APS-1. So far, only five cases of APS-1 have been reported in the Chinese, and the main mutation sites are c. 769C>T (p.R257*), c.55G>A (p.A19T), c.463G>A (p.G155fsX203), c.622G>T (p.G208W) and c.206A>C (p.Q69P).

Identification of two novel mutations in the first Sicilian APECED patient with no R203X mutation in AIRE gene and review of Italian APECED genotypes

Aims of the present study are: 1) to report an additional Sicilian patient with autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), whose genotypic features are original, in that she is the first APECED patient with three coexisting mutations of Autoimmune Regulator (AIRE) gene, two of which had never been reported to date; 2) to review the genotypic epidemiology of APECED in Italy, in order to underline the great genetic heterogeneity of this disorder in Italian patients. Both the novel mutations of our new patient, named S107C and Q108fs respectively, were detected on exon 3 and were inherited by the mother, whereas the third one (T16M) was inherited by the father. Phenotypically, the present case is quite characteristic, in that she exhibited a classical clinical picture, with no original features. Conclusions: a) this is the seventh Sicilian APECED patient identified to date, and the first one with no R203X mutation; b) our data confirm that distribution of mutations may considerably vary according to different geographical distribution, within the same country, thus suggesting a potential founder effect.

Autoimunska tireoidna bolest i poliglandularne autoimunske bolesti

Autoimmune polyglandular syndrome (APS) involves dysfunction of two or more endocrine glands, which is based on the autoimmune mechanism. Many authors in addition to the two main APS syndrome, involves the third stand in which autoimmune thyroid disease (ATD) is associated with other autoimmune diseases. APS type 1 occurs less frequently, starting in early childhood and the key is mutation in autoimmune regulator gene. Three major components characterize this syndrome: hypoparathyroidism, autoimmune adrenal insufficiency and mucocutaneous candidiasis. APS type 2 is associated with the HLA antigen system and basically is a disorder of CD4+ and CD25+ regulatory T-cells. The main components of the syndrome are: Addison's disease, ATD and type 1 diabetes mellitus. An important feature of APS is that the expression of components occurs in different time intervals, with each other long periods. ATD is more common than other autoimmune endocrine diseases and include Graves' disease, chronic autoimmune thyroiditis and postpartum thyroiditis. ATD associated with HLA class II genes and polymorphism of cytotoxic T-lymphocytes antigen 4. In basic there is disorder of cellular and humoral immunity, with auto-antibodies targeting tissue specific antigen and and present infiltration of mononuclear cells, predominantly lymphocytes in the affected tissue. The most common antibodies are thyroid peroxidase, thyroglobulin and TSH receptor antibodies. ATD is often associated with other endocrine (diabetes mellitus type 1, Addison's disease, autoimmune pituitary disease, hypoparathyreoidism, premature ovarian failure) and non-endocrine autoimmune diseases. Given the frequency of ATD is a legitimate screening of ATD in other autoimmune diseases, and not vice versa. Testing involves the determination of TPO antibodies and TSH to separate those with high risk of developing ATD and forecasts for further screening.

Autoimmune regulator gene mutations in a Chinese family with autoimmune polyendocrinopathy syndrome type I

To identify the mutation of the autoimmune regulator gene (AIRE) in a Chinese family with autoimmune polyendocrinopathy syndrome type I (APS-I). The AIRE gene mutations were detected using PCR and direct DNA sequencing. Restriction enzyme analysis was used to confirm the mutations and bioinformatic methods were used to predict the possible impact of the mutations on the structure and function of the AIRE protein. A compound heterozygous mutation of A19T/R257X was detected in the proband. Her father had the A19T mutation in exon 1, but this mutation was not detected in 100 unrelated healthy individuals. Her mother had the R257X mutation in exon 6. This is the first report about AIRE mutations in Chinese APS-I kindred. The A19T mutation identified in this study has not been reported in the human gene mutation database (HGMD); the R257X has not been reported in Asians.

Progress in molecular genetics in autoimmune polyendocrinopathy syndrome type I

Autoimmune polyendocrinopathy syndrome type Ⅰ( APS-Ⅰ) is a rare autosomal recessive disorder caused by mutations in autoimmune regulator gene( AIRE) . A number of mutations have been described in the AIRE gene of patients with APS-Ⅰ, including nonsense mutation, missense mutation, silent mutation, splice site mutation, insertions and deletions mutation, et al. The mutation characteristics of the APS-Ⅰ pathogenic gene have been reviewed in the article. Key words: Autoimmune polyendocrinopathy syndrome type Ⅰ; Mutation; Autoimmune regulator gene

Associations of autoimmune disorders in endocrine diseases

Increasing data are known for dialogue between neuroendocrine and immune systems recently. Results of molecular genetic studies provided evidences for common languages of these systems by various signals including neurotransmitters, hormones, cytokines. It is proved the immune system is able to produce neurotransmitters and hormones and endocrine organs can even result in cytokines. This new integrative approach allows to investigate the physiologic events and diseases as interactions between the psycho-neuro-endocrine-immune systems. The autoimmune polyendocrine syndromes constitute a heterogeneous group of disorders characterized by loss of immune tolerance to self-antigens. In spite of distinct clinical pictures, molecular genetic studies revealed a common molecular mechanism in the associations of organ-specific diseases. Autoimmune polyendocrine syndrome-1 is characterized by associations at least two out of three cardinal signs: Addison's disease, autoimmune hypoparathyroidism and mucocutaneous candidiasis. This is a rare autosomal recessive syndrome induced by mutations in autoimmune regulator gene. Autoimmune polyendocrine syndrome-2 occurs more frequently and defined as the coexistence of Addison's disease, autoimmune thyroid disease and/or type-1 diabetes mellitus. Autoimmune polyendocrine syndrome-3 is characterized by association of autoimmune thyroid disease and type-1 diabetes mellitus. The HLA and other genes proved to be important in associations of the syndrome-2 and 3 in contrast to autoimmune polyendocrine syndrome-1. Identification of predisposing genetic helps to understand the common mechanisms and provide possibility for early therapy and prevention as well.

Molecular background of polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence - 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.

Distinct Clinical Phenotype and Immunoreactivity in Japanese Siblings with Autoimmune Polyglandular Syndrome Type 1 (APS-1) Associated with Compound Heterozygous Novel AIRE Gene Mutations

We herein report on two Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1). The brother, who expressed a characteristic phenotype of APS-1, had developed severe mucocutaneous candidiasis in early infancy and thereafter developed hypoparathyroidism and Addison's disease, along with a severe deterioration of his immunologic function. In contrast, the 44-year-old sister, who showed a noncharacteristic phenotype of APS-1, developed insulin-dependent diabetes with high anti-glutamic acid decarboxylase antibody, mild nail candidiasis, and autoimmune hepatitis with intact immunoreactivity. She had three susceptible human leukocyte antigen (HLA) loci for type 1 autoimmune diabetes. The expression of T cell receptor (TCR)Vβ5.1 increased in both patients, while the brother showed a widely suppressed expression of many TCRVβ families. Both individuals possessed compound heterozygous novel autoimmune regulator (AIRE) gene mutations (L29P and IVS9–1G>C). The same AIRE gene mutations can thus be associated with characteristic and noncharacteristic phenotypes of APS-1, and HLA may possibly influence the phenotype of APS-1.