Search

Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of autoimmune conditions may also result from single gene mutations as for autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the autoimmune regulator gene. It was proposed that genetic variability in the autoimmune regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the autoimmune regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14 year old male from Lazio region, affected by common variable immunodeficiency associated with autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the autoimmune regulator gene protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the autoimmune regulator protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pK a calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pK a and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient's unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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 2.4years and now re-evaluated at the age of 14years 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]