title: The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant.
abstract: 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 pKa calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pKa 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.
authors: Research Laboratories, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Emanuele
authors: E
authors: Bellacchio
authors: Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Alessia
authors: A
authors: Palma
authors: University Department of Paediatrics, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Stefania
authors: S
authors: Corrente
authors: Department of Laboratory Medicine, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Francesco
authors: F
authors: Di Girolamo
authors: Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors: E
authors: E
authors: Helen Kemp
authors: Department of Systems Medicine, Tor Vergata University of Rome, Viale Oxford 81, 00133 Rome, Italy.
authors: Gigliola
authors: G
authors: Di Matteo
authors: Proteomics Laboratory Istituto di Fisiologia Clinica, CNR Via Moruzzi, 1, 56124 Pisa, Italy.
authors: Laura
authors: L
authors: Comelli
authors: Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Rita
authors: R
authors: Carsetti
authors: Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Simona
authors: S
authors: Cascioli
authors: University Department of Paediatrics, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors: Caterina
authors: C
authors: Cancrini
authors: Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy. Electronic address: alessandra.fierabracci@opbg.net.
authors: Alessandra
authors: A
authors: Fierabracci
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015551:Autoimmunity / Q000235:genetics*; D003545:Cysteine / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D003545:Cysteine; D012694:Serine; D014157:Transcription Factors; D000096927:AIRE Protein
keywords: Aire; Immunological disorder; Molecular modeling; Pathogenesis; S250C Aire variant