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Dive into the research topics where Gianfranco Savoldi is active.

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Featured researches published by Gianfranco Savoldi.


Journal of Experimental Medicine | 2012

A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP.

Gaetana Lanzi; Daniele Moratto; Donatella Vairo; Stefania Masneri; Ottavia M. Delmonte; Tiziana Paganini; Silvia Parolini; Giovanna Tabellini; Cinzia Mazza; Gianfranco Savoldi; Davide Montin; Silvana Martino; Pier-Angelo Tovo; Itai M. Pessach; Michel J. Massaad; Narayanaswamy Ramesh; Fulvio Porta; Alessandro Plebani; Luigi D. Notarangelo; Raif S. Geha; Silvia Giliani

A homozygous mutation that gave rise to a stop codon in the WIPF1 gene resulted in WASP protein destabilization and in symptoms resembling those of Wiskott-Aldrich syndrome


Immunological Reviews | 2000

Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model.

Luigi D. Notarangelo; Silvia Giliani; Cinzia Mazza; Patrizia Mella; Gianfranco Savoldi; Carmen Rodriguez‐Pérez; Evelina Mazzolari; Maurilia Fiorini; Marzia Duse; Alessandro Plebani; Alberto G. Ugazio; Mauno Vihinen; Fabio Candotti; Richard Fabian Schumacher

Cytokines play a major role in lymphoid development. Defects of the common gamma chain (gamma(c)) or of the JAK3 protein in humans have been shown to result in a severe combined immune deficiency (SCID), with a profound defect in T and natural killer (NK)-cell development, whereas B-cell generation is apparently unaffected (T-B+NK-SCID). While extensive molecular and biochemical analysis of these patients has been instrumental in understanding better the biological properties of the gamma(c) and JAK3 protein, an unexpected phenotypic heterogeneity of gamma(c) and JAK3 deficiency has emerged, indicating the need for appropriate and extensive investigations even in patients with atypical presentations. At the same time, characterization of the defects has been instrumental in the development of novel therapeutic approaches, from in utero hematopoietic stem cell transplantation to gene therapy.


Current Opinion in Allergy and Clinical Immunology | 2004

Congenital neutropenia: advances in diagnosis and treatment.

Raffaele Badolato; Stefania Fontana; Lucia Dora Notarangelo; Gianfranco Savoldi

Purpose of reviewA decade after the availability of hematopoietic growth factors, the long-term outcome of severe congenital neutropenia has dramatically changed. The prolonged survival of neutropenic patients receiving hematopoietic growth factors has drawn attention to the heterogeneity of this disease and to the complications of treatment. The dose of granulocyte colony stimulating factor that is required to obtain normal levels of circulating neutrophils and to prevent fever and infections is quite variable among patients, but is higher in children with severe congenital neutropenia than in those with other conditions of neutropenia. Moreover, leukemic transformation during treatment is not observed in all patients, but is more typical of severe congenital neutropenia and Shwachman-Diamond patients. Recent findingsIn recent years, the converging efforts of hematologists, immunologists and geneticists have led to the discovery of the genetic and biochemical basis of severe congenital neutropenia; cyclic neutropenia; warts, hypogammaglobulinemia, immunodeficiency, myelokathexis or WHIM syndrome and other rarer conditions associated to neutropenia. SummaryAlthough the diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, their treatment is still based on granulocyte colony stimulating factor administration. Understanding the pathogenesis of these forms of neutropenia and their evolution will focus future studies on the mechanisms of normal and pathological myelopoiesis and on the development of the most appropriate treatment for each type of neutropenia.


Immunobiology | 2000

Combined Immunodeficiencies Due to Defects in Signal Transduction: Defects of the γc-JAK3 Signaling Pathway as a Model

Luigi D. Notarangelo; Silvia Giliani; Patrizia Mella; R. Fabian Schumacher; Cinzia Mazza; Gianfranco Savoldi; Carmen Rodriguez‐Pérez; Raffaele Badolato; Evelina Mazzolari; Fulvio Porta; Fabio Candotti; Alberto G. Ugazio

Combined immune deficiencies comprise a spectrum of genetic disorders characterized by developmental or functional defects of both T and B lymphocytes. Recent progress in cell biology and molecular genetics has unraveled the pathophysiology of most of these defects. In particular, the most common form of severe combined immune deficiency in humans, with lack of circulating T cells, a normal or increased number of B lymphocytes, and an X-linked pattern of inheritance (SCIDXI) has been shown to be due to defects of the IL2RG gene, encoding for the common gamma chain (gammac), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through gammac-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional properties of cytokines that signal through the gammac-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7Ralpha). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity of immunological phenotypes that may associate with defects in the same gene, thus creating a need for detailed immunological and molecular investigations in order to dissect the spectrum of combined immune deficiencies in humans.


British Journal of Haematology | 2001

Rapid protein-based assays for the diagnosis of T-B+ severe combined immunodeficiency.

Kimberly Gilmour; Treena Cranston; Sam Loughlin; Jackie Gwyther; T Lester; Teresa Espanol; Manuel Hernandez; Gianfranco Savoldi; E. Graham Davies; Mario Abinun; Christine Kinnon; Alison Jones; Hubert B. Gaspar

The severe combined immunodeficiencies (SCID) are a heterogeneous group of conditions arising from a variety of molecular defects. The X‐linked form of SCID (X‐SCID) is caused by defects in the common gamma chain (γc), and is characterized by a T–B+NK− immunophenotype. This lymphocyte profile is seen in an autosomal recessive form of SCID caused by mutations in the JAK3 molecule. Thus, X‐SCID and JAK3‐deficient SCID are clinically and immunologically indistinguishable. Knowledge of the precise molecular defect is essential for antenatal diagnosis, carrier testing and for treatment using somatic gene therapy. To identify the molecular defect in children presenting with a T–B+NK− form of SCID, we have developed rapid assays based on flow cytometric analysis of γc, immunoblotting for JAK3 and γc, and detection of interleukin‐2 (IL‐2)‐induced tyrosine phosphorylation of JAK3. Sixteen T–B+NK− SCID patients from 15 families were examined. Nine had no detectable γc, four had abnormal γc expression and no IL‐2‐induced JAK3 tyrosine phosphorylation, and one had normal γc expression but no IL‐2‐induced JAK3 tyrosine phosphorylation, although JAK3 was present. All these patients had mutations identified in their γc gene. Two patients exhibited normal γc expression, but JAK3 was not detected by immunoblotting and these patients were confirmed as having JAK3 gene mutations. Thus, these protein‐based assays have led to rapid molecular diagnoses in T–B+ SCID that have subsequently been confirmed by genetic analysis.


American Journal of Medical Genetics Part A | 2013

Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R

Gianfranco Savoldi; Claudia Izzi; M. Signorelli; Maria Pia Bondioni; Chiara Romani; Gaetana Lanzi; Daniele Moratto; Lucio Verdoni; Moira Pinotti; F. Prefumo; Andrea Superti-Furga; Alba Pilotta

Wave‐shaped ribs were detected at prenatal ultrasound in a 20+1 week female fetus. At birth, skeletal radiographs showed marked hypomineralization and suggested hypophosphatasia. However, elevated blood calcium and alkaline phosphatase excluded hypophosphatasia and raised the possibility of Jansen metaphyseal dysplasia. Molecular analysis of the PTH/PTHrP receptor gene (PTH1R) showed heterozygosity for a previously undescribed transversion variant (c.1373T>A), which predicts p.Ile458Lys. In vitro evaluation of wild type and mutant PTH/PTHrP receptors supported the pathogenic role of the p.Ile458Lys substitution, and confirmed the diagnosis of Jansen metaphyseal dysplasia. This disorder may present prenatally with wavy ribs and in the newborn with hypomineralization, and may therefore be confused with hypophosphatasia. The mottled metaphyseal lesions typically associated with this disease appear only in childhood.


Respiration | 2011

Population genetic screening for alpha1-antitrypsin deficiency in a high-prevalence area.

Luciano Corda; Daniela Medicina; Giuseppe Emanuele La Piana; Enrica Bertella; Giovanni Moretti; Luca Bianchi; Valentina Pinelli; Gianfranco Savoldi; Paola Baiardi; Fabio Facchetti; Nuccia Gatta; Isabella Annesi-Maesano; Bruno Balbi

Background: Current guidelines for α1-antitrypsin deficiency (AATD) state that adult population screening should only be done in high-risk areas. Up-to-date genetic methods are always recommended. Objectives: To determine the prevalence of AATD in a suspected high-risk area by population screening, applying new genetic analyses and comparing the prevalence of liver and lung abnormalities in subjects with or without AATD. Methods: Adult residents of Pezzaze, a village in an Italian alpine valley, voluntarily participated in the screening, and were examined for: nephelometric α1-antitrypsin (AAT) serum level, DNA analysis (mutagenic polymerase chain reaction and restriction fragment length polymorphism tests for Z and S AATD causative mutations, and denaturing high-performance liquid chromatography and/or direct gene sequencing if needed), serum aspartate and alanine transaminases, a respiratory questionnaire and the Medical Research Council dyspnea index scale. The prevalence of AATD was compared with that expected in Italy (Hardy-Weinberg equilibrium), and transaminases and the prevalence of respiratory symptoms were compared between study groups. Results: Of 1,353 residents, 817 (60.4%) participated; 67 (8.2%) had low AAT serum levels (<90 mg/dl); 118 were carriers of AATD-associated alleles, 4 (0.5%) homozygotes or compound heterozygotes (1 Z, 1 S, 2 ZPbrescia), 114 (14%) heterozygotes (46 Z, 52 S, 9 Pbrescia, 4 Mwurzburg, 2 I, 1 Plowell). The prevalence and frequency of all AATD-related alleles was higher than expected for Italy (p < 0.001). There were no differences in symptoms of respiratory disease and transaminases between individuals with normal and low serum AAT. Conclusion: The screening design is one of the main strengths of this study. The large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible. Early recognition of individuals at risk means primary or secondary prevention measures can be taken.


Current Opinion in Allergy and Clinical Immunology | 2005

Cytokine-mediated signalling and early defects in lymphoid development.

Silvia Giliani; Patrizia Mella; Gianfranco Savoldi; Evelina Mazzolari

Purpose of reviewThe aim of the review is to report on recent advances in cytokine-mediated signalling, as illustrated by the study of natural human mutants. In particular, the role of cytokines and cytokine-mediated signalling in human T-cell development is analysed in detail, and currently available forms of treatment including experimental trials are described. Recent findingsDefects of the cytokine/JAK/STAT axis have been recently described as responsible for human Severe Combined Immune Deficiency. In particular, defects in γc, JAK3 and IL7RA have been analysed in terms of development of novel diagnostic tools as well as of new therapeutic agents for the treatment of autoimmune diseases and graft-versus-host disease. SummaryDissection of the genetic defects underlying the various forms of Severe Combined Immune Deficiency has helped develop new and more accurate diagnostic assays and novel forms of treatment.


American Journal of Medical Genetics Part A | 2011

Clinical and Molecular Description of a Wilms Tumor in a Patient With Tuberous Sclerosis Complex

Filippo Spreafico; Lucia Dora Notarangelo; Richard Fabian Schumacher; Gianfranco Savoldi; Beatrice Gamba; Monica Terenziani; Paola Collini; Silvia Fasoli; Lucio Giordano; Bercich Luisa; Fulvio Porta; Maura Massimino; Paolo Radice; Daniela Perotti

We report on a girl affected with tuberous sclerosis, carrying a germline de novo TSC2 mutation, c.4934‐4935delTT, leading to a p.F1645CfsX7, who developed a unilateral Wilms tumor (WT). Molecular investigation of the tumor biopsy at diagnosis revealed the loss of the constitutional wild‐type TSC2 allele, and loss of heterozygosity for the WT1 gene. Deletion of the WTX gene was also present, but it involved the functionally inactive X chromosome. No mutation affecting the remaining WT1 and WTX alleles, as well as the CTNNB1 gene was found. Pathological examination of the surgical specimen documented the presence of diffuse anaplasia and p53 immunoreactivity. To the best of our knowledge, this is the second report of a patient with tuberous sclerosis who developed a WT, and it represents the first case in which a detailed clinical and molecular description is provided.


Italian Journal of Pediatrics | 2014

Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype in two patients with two novel mutations

Lucia Dora Notarangelo; Gianfranco Savoldi; Sara Cavagnini; Veronica Bennato; Sabrina Vasile; Alba Pilotta; Alessandro Plebani; Fulvio Porta

Severe Congenital Neutropenia type 4 (SCN4, OMIM 612541) is a rare autosomal recessive disease due to mutations in the G6PC3 gene. The phenotype comprises neutropenia of variable severity and other anomalies including congenital heart defects, prominent superficial veins, uro-genital anomalies, facial dysmorphism, growth and developmental delay and intermittent thrombocytopenia. In some patients, SCN represents the only manifestation of the disease. Variable findings have been reported at bone marrow examination ranging from a maturation arrest at the myelocyte/promyelocyte stage (either in a hypocellular or hypercellular context) to myelokathexis. Here we report two patients harbouring two novel mutations in the G6PC3 gene, including the first Italian patient even described. Both the patients share profound neutropenia with severe infections early in life; in one case non-hematopoietic stigmata of the syndrome, including evident facial dysmorphism and vascular anomalies, appeared gradually over time, prominently in the second decade. Therefore, G6PC3 defects should be considered in any case of congenital, unexplained neutropenia regardless of the clinical phenotype. Both patients are on G-CSF treatment with no evidence of malignant evolution. Even if G6PC3 deficiency seems not to have a propensity towards malignancy, a careful evaluation is warranted.

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