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

Emanuele Bellacchio, Alessia Palma, Stefania Corrente, Francesco Di Girolamo, E. Helen Kemp, Gigliola Di Matteo, Laura Comelli, Rita Carsetti, Simona Cascioli, Caterina Cancrini, Alessandra Fierabracci

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)286-294
Number of pages9
JournalGene
Volume549
Issue number2
DOIs
Publication statusPublished - Oct 10 2014

Fingerprint

Autoimmunity
Computer Simulation
Regulator Genes
Cysteine
Proteins
Mutation
Central Tolerance
Autoimmune Polyendocrinopathies
Peripheral Tolerance
Common Variable Immunodeficiency
Phenotype
Alopecia
Autoantigens
Molecular Dynamics Simulation
Heterozygote
Thymus Gland
Genes

Keywords

  • Aire
  • Immunological disorder
  • Molecular modeling
  • Pathogenesis
  • S250C Aire variant

ASJC Scopus subject areas

  • Genetics

Cite this

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. / Bellacchio, Emanuele; Palma, Alessia; Corrente, Stefania; Di Girolamo, Francesco; Helen Kemp, E.; Di Matteo, Gigliola; Comelli, Laura; Carsetti, Rita; Cascioli, Simona; Cancrini, Caterina; Fierabracci, Alessandra.

In: Gene, Vol. 549, No. 2, 10.10.2014, p. 286-294.

Research output: Contribution to journalArticle

@article{f7346863d85f4dfea9f2377c255a271c,
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.",
keywords = "Aire, Immunological disorder, Molecular modeling, Pathogenesis, S250C Aire variant",
author = "Emanuele Bellacchio and Alessia Palma and Stefania Corrente and {Di Girolamo}, Francesco and {Helen Kemp}, E. and {Di Matteo}, Gigliola and Laura Comelli and Rita Carsetti and Simona Cascioli and Caterina Cancrini and Alessandra Fierabracci",
year = "2014",
month = "10",
day = "10",
doi = "10.1016/j.gene.2014.07.064",
language = "English",
volume = "549",
pages = "286--294",
journal = "Gene",
issn = "0378-1119",
publisher = "Elsevier B.V.",
number = "2",

}

TY - JOUR

T1 - The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency

T2 - In silico analysis suggests a molecular pathogenic mechanism for the variant

AU - Bellacchio, Emanuele

AU - Palma, Alessia

AU - Corrente, Stefania

AU - Di Girolamo, Francesco

AU - Helen Kemp, E.

AU - Di Matteo, Gigliola

AU - Comelli, Laura

AU - Carsetti, Rita

AU - Cascioli, Simona

AU - Cancrini, Caterina

AU - Fierabracci, Alessandra

PY - 2014/10/10

Y1 - 2014/10/10

N2 - 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.

AB - 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.

KW - Aire

KW - Immunological disorder

KW - Molecular modeling

KW - Pathogenesis

KW - S250C Aire variant

UR - http://www.scopus.com/inward/record.url?scp=84906050589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906050589&partnerID=8YFLogxK

U2 - 10.1016/j.gene.2014.07.064

DO - 10.1016/j.gene.2014.07.064

M3 - Article

C2 - 25068407

AN - SCOPUS:84906050589

VL - 549

SP - 286

EP - 294

JO - Gene

JF - Gene

SN - 0378-1119

IS - 2

ER -