Papers by alessandra meloni
The New England journal of medicine, Apr 27, 2017
Background Genomewide association studies of autoimmune diseases have mapped hundreds of suscepti... more Background Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Methods Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were al...
Bookmarks Related papers MentionsView impact
Journal of Oral Pathology & Medicine, 2016
he aim of this study was to investigate whether a variation in the genomic copy number (CNV) of t... more he aim of this study was to investigate whether a variation in the genomic copy number (CNV) of the β-defensin cluster could be associated with the predisposition to Chronic Mucocutaneous Candidiasis (CMC) in Sardinian APECED patients. The β-defensin copy number variation was determined by MLPA analysis in 18 Sardinian APECED patients with CMC and in 21 Sardinian controls. Statistical analyses were performed with ANOVA-one way test. No statistically significant results were observed between the patients and controls groups. According to the results we have obtained, it appears that either β-defensin genomic CNV is not a modifier locus for CMC susceptibility in APECED patients, or that any effect is too small for it to be detected using such sample size. An extensive study on APECED patients from different geographical areas might reveal the real implication of the β-defensin CNV in the susceptibility to Candida albicans infections. This article is protected by copyright. All rights reserved.
Bookmarks Related papers MentionsView impact
Brit J Haematol, 1994
Bookmarks Related papers MentionsView impact
Journal of Biomedical Science, 2014
Bookmarks Related papers MentionsView impact
PLoS ONE, 2012
Bookmarks Related papers MentionsView impact
Journal of Biological Chemistry, 2010
Bookmarks Related papers MentionsView impact
Human Mutation, 1994
Bookmarks Related papers MentionsView impact
British Journal of Haematology, 1992
ABSTRACT In this study we have investigated the molecular basis for a mild form of beta-thalassae... more ABSTRACT In this study we have investigated the molecular basis for a mild form of beta-thalassaemia in three patients of Italian descent. In two, belonging to different families and affected by a mild and late-presenting form of thalassaemia major, direct sequencing of amplified DNA detected a C----T substitution at position -87 of the beta-globin gene in the compound heterozygous state either with codon 39 nonsense mutation or beta +IVSI, nt 110 mutation. The -87 (C----T) mutation has been previously described, in combination with the beta +IVSI, nt 110 mutation, in a single patient with thalassaemia intermedia. Both our patients showed a more severe phenotype as compared to that resulting from compound heterozygosity for a severe beta-thalassaemia mutation and another promoter mutation (-87, C----G) at the same position. In the third patient with the thalassaemia intermedia phenotype, we detected a novel promoter mutation, consisting in a C----A substitution at position -86, in combination with the codon 39 nonsense mutation. The results of this study indicate that different nucleotide substitutions affecting the proximal CACCC box of the beta-globin gene in combination with severe beta-thalassaemia, produce a mild form of thalassaemia ranging in severity from thalassaemia intermedia to late-presenting thalassaemia major.
Bookmarks Related papers MentionsView impact
Journal of Medical Genetics, 1995
Bookmarks Related papers MentionsView impact
Human Genetics, 1998
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also called APS-1,) is a ... more Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also called APS-1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is characterized by two of the three major clinical symptoms that may be present: Addison’s disease, and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. We have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes and fetal liver, and encodes a protein with two putative zinc fingers and other motifs suggestive of a transcriptional regulator. Seven mutations have been described to date, including R257X, the predominant Finnish and northern Italian APECED allele, which has also been observed in other patients of diverse origin on different haplotypes. A 13-bp deletion (1094–1106del) has also been observed in several patients of different geo-ethnic origin. The other described mutations appear to be rare. We present mutational analyses of the AIRE gene in ten Sardinian APECED families and show that there is a mutation, R139X, associated with one predominant haplotype unique to the Sardinian patients (18/20 independent alleles). The carrier frequency of R139X in Sardinia is 1.7%, giving an estimated population frequency of APECED of 1/14,400. Using linkage disequilibrium data, the estimated age of the R139X mutation is between 20 and 25 generations. A previously described 13-bp deletion was also observed on an allele of one patient. The identification of a single common Sardinian APECED mutation will facilitate its genetic diagnosis. Given the carrier frequency of R139X in the Sardinian population, AIRE may be implicated in the pathogenesis of other autoimmune diseases in the Sardinian population, particularly those affecting the endocrine system.
Bookmarks Related papers MentionsView impact
British Journal of Haematology, 1995
Summary. This study describes the clinical phenotype of the C?→? T mutation at position – 92 of t... more Summary. This study describes the clinical phenotype of the C?→? T mutation at position – 92 of the β-globin gene. Excluding two cases with HbA2 levels within the range of the /3-thalassaemia carrier state, heterozygotes for this mutation showed normal or borderline red blood cells count, Hb levels, MCV, MCH and HbA2 values, and unbalanced globin chain synthesis. Compound heterozygotes for the - 92 C → T mutation and a β° thalassaemia mutation (β°39) (two cases) or severe β-thalassaemia (p+ IVSII nt 745) (two cases) developed thalassaemia intermedia. According to these characteristics, the –92 promoter mutation should be added to the list of silent β-thalassaemias.
Bookmarks Related papers MentionsView impact
In this study, we have carried out molecular analysis of the AIRE (autoimmune regulator) gene in ... more In this study, we have carried out molecular analysis of the AIRE (autoimmune regulator) gene in 11 patients (from 8 families) affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, originating from a restricted area of Southern Italy (the Salento peninsula in Puglia). Of the 16 mutant AIRE alleles from the 8 probands studied, 12 carried a missense mutation (W78R in 9, P539L in 2, and P252L in 1), 2 carried the Q358X nonsense mutation, and 2 carried the 1058delT frameshift mutation. All these mutations except the 1058delT are novel. Each of the detected mutations either predicts a premature termination of the protein or results in a nonconservative amino acid change, most likely adversely affecting the function of the protein. The W78R missense mutation is relatively common in these patients, having been detected (in homozygosity or compound heterozygosity) in 6 of the 8 probands tested, indicating the presence of a founder effect. The results of this study contribute to the delineation of the molecular pathology of the AIRE gene and enhance our ability to perform a molecular diagnosis in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.
Bookmarks Related papers MentionsView impact
Human Genetics, 1992
This paper reports our experience of molecular screening and fetal diagnosis of β-thalassemia in ... more This paper reports our experience of molecular screening and fetal diagnosis of β-thalassemia in 457 at risk couples of Italian descent. Molecular screening was carried out by dot blot analysis on amplified DNA with oligonucleotide probes complementary to the eight most common mutations in Italians [β∘39 (C→T); ∘6 (-A); β+-87 (C→G); β+ IVSI nt 110 (G→A); β∘IVSI nt 1 (G→A); β+ IVSI nt 6 (T→C); β∘ IVSII nt 1 (G→A); β+ IVSII nt 745 (C→G)]. By using this approach, we have been able to define the mutation in 92.8% of cases. The rest (all but four) were defined by direct sequencing and this led to the detection of nine rare mutations [β∘76 (-C); β+ IVSI nt 5 (G→A); β+ IVSI nt 5 (G→C); β+ IVSI -1 (cod 30) (G→C); β+-87 (C→T), β∘-290 bp del.; β+-101 (C→T)], and to the characterization of a novel mutation consisting of the deletion of the G at the invariant AG of the IVSII splice acceptor site of the β-globin gene (β IVSII nt 850-1 bp). In the remaining four cases, the β-globin gene showed entirely normal sequences and the β-globin gene cluster was intact, as indicated by Southern blot analysis. Fetal diagnosis was carried out by dot blot analysis with the oligonucleotide probes defined in the parents. The procedure is simple and reliable, and the results can be obtained within 1 week of sampling. No misdiagnosis has so far occurred. The results indicate that fetal diagnosis of β-thalassemia by DNA analysis may be obtained in practically all cases (even in a population showing marked heterogeneity of β-thalassemia) by the combination of dot blot analysis for detecting common mutations, and direct sequencing for defining those that are uncommon.
Bookmarks Related papers MentionsView impact
British Journal of Haematology, 2006
This study describes the largest series reported to date, of individuals belonging to unrelated f... more This study describes the largest series reported to date, of individuals belonging to unrelated families carrying a β-thalassaemia-like phenotype in whom the β-globin gene was found to be structurally intact by sequence analysis. This genetic determinant appears haematologically heterogeneous, displaying either a silent β-thalassaemia-like phenotype or a typical β-thalassaemia carrier-like phenotype in different families. Compound heterozygosity for both β-thalassaemia-like determinant and typical β-thalassaemia allele resulted either in thalassaemia intermedia or thalassaemia major. By linkage analysis both the silent and the typical β-like determinants were found not to be linked to the β-globin cluster. Sequence analysis of the hypersensitive site cores of locus control region and of the genes coding for the transcription factors erythroid Kruppel-like factor and nuclear factor (erythroid-derived 2) were normal. β-globin mRNA levels determined by real-time polymerase chain reaction were reduced in both types of β-like carriers. These results indicate the existence of causative genetic determinants not yet molecularly defined, but most likely, resulting from either the reduction or loss of function of a gene coding for unknown transcriptional regulator(s) of the β-globin gene. The knowledge of these rare β-thalassaemia-like determinants have implications for clinical and, especially, prenatal diagnosis of β-thalassaemia.
Bookmarks Related papers MentionsView impact
British Journal of Haematology, 1994
Summary. This paper describes the phenotypic manifestations of a very mild β-thalassaemia mutatio... more Summary. This paper describes the phenotypic manifestations of a very mild β-thalassaemia mutation detected in several members of two families of Italian descent. The molecular defect, defined by denaturing gradient gel electrophoresis analysis and direct sequencing. consists of a C G substitution at position 844 of IVSII of the β-globin gene within the consensus sequence of IVSII acceptor splice site. Heterozygotes for this mutation show a haematological phenotype ranging in severity from silent β-thalassaemia to that of a mild β-thalassaemia carrier silent β-thalassaemia to that of a mild β-thalassaemia carrier state, whereas homozygotes have the typical manifestations commonly resulting from heterozygosity for a β-thalassaemia mutation. Compound heterozygotes for the IVSII nt844 (C G) mutation and a severe β-thalassaemia mutation have the phenotype of thalassaemia intermedia.This paper indicates that the presence of borderline red blood cell indices or HbA2 values should make one suspect the presence of a very mild or silent β-thalassaemia.
Bookmarks Related papers MentionsView impact
Human Molecular Genetics, 1993
Bookmarks Related papers MentionsView impact
Human Genetics, 1992
This paper reports our experience of molecular screening and fetal diagnosis of β-thalassemia in ... more This paper reports our experience of molecular screening and fetal diagnosis of β-thalassemia in 457 at risk couples of Italian descent. Molecular screening was carried out by dot blot analysis on amplified DNA with oligonucleotide probes complementary to the eight most common mutations in Italians [β∘39 (C→T); ∘6 (-A); β+-87 (C→G); β+ IVSI nt 110 (G→A); β∘IVSI nt 1 (G→A); β+ IVSI nt 6 (T→C); β∘ IVSII nt 1 (G→A); β+ IVSII nt 745 (C→G)]. By using this approach, we have been able to define the mutation in 92.8% of cases. The rest (all but four) were defined by direct sequencing and this led to the detection of nine rare mutations [β∘76 (-C); β+ IVSI nt 5 (G→A); β+ IVSI nt 5 (G→C); β+ IVSI -1 (cod 30) (G→C); β+-87 (C→T), β∘-290 bp del.; β+-101 (C→T)], and to the characterization of a novel mutation consisting of the deletion of the G at the invariant AG of the IVSII splice acceptor site of the β-globin gene (β IVSII nt 850-1 bp). In the remaining four cases, the β-globin gene showed entirely normal sequences and the β-globin gene cluster was intact, as indicated by Southern blot analysis. Fetal diagnosis was carried out by dot blot analysis with the oligonucleotide probes defined in the parents. The procedure is simple and reliable, and the results can be obtained within 1 week of sampling. No misdiagnosis has so far occurred. The results indicate that fetal diagnosis of β-thalassemia by DNA analysis may be obtained in practically all cases (even in a population showing marked heterogeneity of β-thalassemia) by the combination of dot blot analysis for detecting common mutations, and direct sequencing for defining those that are uncommon.
Bookmarks Related papers MentionsView impact
Prenatal Diagnosis, 1992
This study describes three couples a t risk for homozygous β-thalassaemia in which one of the par... more This study describes three couples a t risk for homozygous β-thalassaemia in which one of the partners carried a short deletion β-thalassaemia defect. Detection of short deletions in trophoblast DNA was accomplished by the very simple procedure of non-denaturing polyacrylamide gel electrophoresis. This method may be applied to detect β-thalassaemia mutations due to deletion or addition of more than two nucleotides.
Bookmarks Related papers MentionsView impact
Molecular Immunology, 2008
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomic autoi... more Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomic autoimmune disease resulting from the defective function of a gene codifying for a transcription factor named autoimmune regulation (AIRE). The AIRE protein contains several domains among which two PHD fingers involved in the transcriptional activation. We investigated the function of the two PHD finger domains and the COOH terminal portion of AIRE by using several mutated constructs transfected in mammalian cells and a luciferase reporter assay. The results predict that the second PHD as well as the COOH terminal regions have marked transactivational properties. The COOH terminal region contains the fourth LXXLL and the PXXPXP motifs which play a critical role in mediating the transactivation capacity of the AIRE protein. Our study provides a definition of the role of the PHD fingers in transactivation and identifies a new transactivation domain of the AIRE protein localized in the COOH terminal region.
Bookmarks Related papers MentionsView impact
Human Mutation, 1992
Bookmarks Related papers MentionsView impact
Uploads
Papers by alessandra meloni