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The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals.

Turner syndrome is a condition caused by numeric and structural abnormalities of the X chromosome, and is characterized by a series of clinical features, the most common being short stature and gonadal dysgenesis. An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in Turner patients. We present a unique case of mosaic Turner syndrome with a complex rearrangement consisting of a partial deletion of chromosome 2q and duplication of chromosome 10p {[46],XX,der(2)t(2;10)(2pter→2q37::10p13→10pter)[127]/45,X,der(2)t(2;10)(2pter→2q37::10p13→10pter)[23]}. The patient is affected by partial empty sella, in association with a group of multiorgan autoimmunity-related manifestations including Hashimoto's thyroiditis, celiac disease, insulin-dependent diabetes mellitus (Type 1 diabetes, T1D), possible autoimmune inner ear disease with sensorineural deficit, preclinical Addison disease and alopecia universalis. The patient was previously described at the age of 2.4 years and now re-evaluated at the age of 14 years after she developed autoimmune conditions. AIRE gene screening revealed heterozygous c.834 C>G polymorphism (p.Ser278Arg) and IVS9+6G>A variation, thus likely excluding autoimmune polyendocrine syndrome Type 1 (APECED). Heterozygous R620W polymorphism of the protein tyrosine phosphatase non receptor type 22 (PTPN22) gene was detected in patient's DNA. SNP-array analysis revealed that autoimmunity-related genes could be affected by the partial monosomy 2q and trisomy 10p. These data suggest that early genetic analysis in TS patients with complex associations of multiorgan autoimmune manifestations would permit a precise diagnostic classification and also be an indicator for undiscovered pathogenetic mechanisms.

The cysteine/cystine (Cys/CySS) couple represents one of the major cell thiol/disulfide systems and is involved in the regulation of several metabolic pathways and the cell redox state. Nephropathic cystinosis (NC) is an autosomal recessive disease characterized by renal cellular dysfunction due to mutations in the CTNS gene, which encodes cystinosin, a CySS lysosomal transporter. To analyze the mechanisms involved in cell damage in NC, we have investigated the effects of CTNS gene overexpression or inhibition on cell thiol/disulfide systems and vice versa. Overexpression of the CTNS gene had no remarkable effect on intracellular Cys/CySS and GSH/GSSG redox state. Silencing the CTNS gene increased cell CySS and Cys and decreased cell GSH and GSSG and increased mildly the redox state of the Cys/CySS-couple. Extracellular CySS and Cys deprivation for 48 h caused an oxidation of the Cys/CySS (73 mV) and GSH/GSSG (100 mV) redox couples and increased CTNS mRNA levels by 1.9+/-0.2-fold (p0.001). Conversely, a reduced cell environment associated with a GSH/GSSG reduction from -250.1+/-3.10 to -330.6+/-4.70 mV (p0.001) and a Cys/CySS reduction from -167.0+/-11.30 to -240.0+/-8.17 mV (p0.005) was associated with a 40% decrease in CTNS mRNA levels (p0.05). By regression analysis, CTNS gene expression was correlated with intracellular Cys level and with Cys/CySS redox state.

Nephropathic cystinosis (NC) is an autosomal recessive disorder characterized by the accumulation of the amino acid cystine in lysosomes, due to defective transport of cystine across the lysosomal membrane. Patients suffer from severe renal Fanconi syndrome from the first months of life and progress to end-stage renal failure during their second decade. Treatment with cysteamine delays the progression of chronic renal failure and improves most NC-related symptoms. Two less severe forms of cystinosis, a juvenile and an ocular form, have also been described. NC is caused by mutations in the CTNS gene that encodes for the cystinosin protein, a transmembrane lysosomal transporter. Cystinosin is a proton symporter, co-transporting cystine and protons in the same direction. Over 50 mutations have been described, including a common 57 kb deletion. Various metabolic and structural alterations have been described in cystinotic cells. These include decreased ATP and glutathione synthesis, increased apoptotic activity and mitochondrial damage. Although much progress has been made in the molecular and clinical fields, the mechanisms linking the accumulation of cystine in lysosomes and proximal tubular cell dysfunction are still poorly understood.