Jacqueline Feinberg

Publications (45)439.58 Total impact

• Article: Inherited IL-12p40 Deficiency: Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds.

  Carolina Prando, Arina Samarina, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Aurelie Cobat, Capucine Picard, Zobaida Alsum, Suliman Al-Jumaah, Sami Al-Hajjar, Husn Frayha, [......], Mohammed A Al Shehri, Mofareh Al-Zahrani, Ibrahim Bin-Hussain, Seyed Alireza Mahdaviani, Nima Parvaneh, Laurent Abel, Davood Mansouri, Ridha Barbouche, Saleh Al-Muhsen, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency.In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
  Medicine 03/2013; 92(2):109-122. · 4.35 Impact Factor
• Source

  Available from: Xiao-Fei Kong

  Article: Mendelian susceptibility to mycobacterial disease in egyptian children.

  Nermeen Galal, Jeannette Boutros, Aisha Marsafy, Xiao-Fei Kong, Jacqueline Feinberg, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis, Jacinta Bustamante
  [show abstract] [hide abstract]
  ABSTRACT: Tuberculosis remains a major health problem in developing countries especially with the emergence of multidrug resistant strains. Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare disorder with impaired immunity against mycobacterial pathogens. Reported MSMD etiologies highlight the crucial role of the Interferon gamma /Interleukin 12 (IFN-γ/ IL-12) axis and the phagocyte respiratory burst axis. Screen patients with possible presentations for MSMD. Patients with disseminated BCG infection following vaccination, atypical mycobacterial infections or recurrent tuberculosis infections were recruited from the Primary Immune Deficiency Clinic at Cairo University Specialized Pediatric Hospital, Egypt and immune and genetic laboratory investigations were conducted at Human Genetic of Infectious Diseases laboratory in Necker Medical School, France from 2005-2009. IFN-γ level in patient's plasma as well as mutations in the eight previously identified MSMD-causing genes were explored. Nine cases from eight (unrelated) kindreds were evaluated in detail. We detected a high level of IFN-γ in plasma in one patient. Through Sanger sequencing, a homozygous mutation in the IFNGR1 gene at position 485 corresponding to an amino acid change from serine to phenylalanine (S485F), was detected in this patient. We report the first identified case of MSMD among Egyptian patients, including in particular a new IFNGR1 mutation underlying IFN-γR1 deficiency. The eight remaining patients need to be explored further. These findings have implications regarding the compulsory Bacillus.
  Mediterranean Journal of Hematology and Infectious Diseases 01/2012; 4(1):e2012033.
• Article: New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein.

  Marjorie Hubeau, Flora Ngadjeua, Anne Puel, Laura Israel, Jacqueline Feinberg, Maya Chrabieh, Kiran Belani, Christine Bodemer, Isabelle Fabre, Alessandro Plebani, Stéphanie Boisson-Dupuis, Capucine Picard, Alain Fischer, Alain Israel, Laurent Abel, Michel Veron, Jean-Laurent Casanova, Fabrice Agou, Jacinta Bustamante
  [show abstract] [hide abstract]
  ABSTRACT: Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID-causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID-causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding-dependent receptors, the TNF and IL-1β receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-κB activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.
  Blood 05/2011; 118(4):926-35. · 9.90 Impact Factor
• Article: Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease.

  Audrey V Grant, Stéphanie Boisson-Dupuis, Eléonore Herquelot, Ludovic de Beaucoudrey, Orchidée Filipe-Santos, Daniel K Nolan, Jacqueline Feinberg, Anne Boland, Saleh Al-Muhsen, Ozden Sanal, Yildiz Camcioglu, Ayse Palanduz, Sara Sebnem Kilic, Jacinta Bustamante, Jean-Laurent Casanova, Laurent Abel
  [show abstract] [hide abstract]
  ABSTRACT: Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity. The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations. The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3). The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.
  Journal of Medical Genetics 05/2011; 48(8):567-71. · 6.36 Impact Factor
• Article: IRF8 mutations and human dendritic-cell immunodeficiency.

  Sophie Hambleton, Sandra Salem, Jacinta Bustamante, Venetia Bigley, Stéphanie Boisson-Dupuis, Joana Azevedo, Anny Fortin, Muzlifah Haniffa, Lourdes Ceron-Gutierrez, Chris M Bacon, [......], Anete Grumach, Alberto Duarte, Katia Abarca, Dewton Moraes-Vasconcelos, David Burk, Albert Berghuis, Frédéric Geissmann, Matthew Collin, Jean-Laurent Casanova, Philippe Gros
  [show abstract] [hide abstract]
  ABSTRACT: The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).
  New England Journal of Medicine 04/2011; 365(2):127-38. · 53.30 Impact Factor
• Article: Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease.

  Jacinta Bustamante, Andres A Arias, Guillaume Vogt, Capucine Picard, Lizbeth Blancas Galicia, Carolina Prando, Audrey V Grant, Christophe C Marchal, Marjorie Hubeau, Ariane Chapgier, [......], Claire Fieschi, Jean-François Emile, Stéphanie Boisson-Dupuis, Saleh Al-Muhsen, Bruce Woda, Peter E Newburger, Antonio Condino-Neto, Mary C Dinauer, Laurent Abel, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.
  Nature Immunology 03/2011; 12(3):213-21. · 26.01 Impact Factor
• Article: Hodgkin lymphoma in 2 children with chronic granulomatous disease.

  Saul Oswaldo Lugo Reyes, Felipe Suarez, Rose-Marie Herbigneaux, Hélène Pacquement, Yves Réguerre, Jean-Pierre Rivière, Maylis de Suremain, Yoann Rose, Jacqueline Feinberg, Nizar Malahoui, Alain Fischer, Stéphane Blanche, Jean-Laurent Casanova, Capucine Picard, Jacinta Bustamante
  The Journal of allergy and clinical immunology 02/2011; 127(2):543-544.e1-3. · 9.17 Impact Factor
• Source

  Available from: Estefania Herrera-Ramos

  Article: Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds.

  Ithaisa Sologuren, Stéphanie Boisson-Dupuis, Jose Pestano, Quentin Benoit Vincent, Leandro Fernández-Pérez, Ariane Chapgier, María Cárdenes, Jacqueline Feinberg, M Isabel García-Laorden, Capucine Picard, [......], Mónica Valerón-Lemaur, José Gonçalo-Marques, Luisa Silveira, José Manuel García-Castellano, José Caminero, José Luis Pérez-Arellano, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, Carlos Rodríguez-Gallego
  [show abstract] [hide abstract]
  ABSTRACT: We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.
  Human Molecular Genetics 02/2011; 20(8):1509-23. · 7.64 Impact Factor
• Source

  Available from: Melike Keser

  Article: IL-12Rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey.

  Stéphanie Boisson-Dupuis, Jamila El Baghdadi, Nima Parvaneh, Aziz Bousfiha, Jacinta Bustamante, Jacqueline Feinberg, Arina Samarina, Audrey V Grant, Lucile Janniere, Naima El Hafidi, [......], Melike Keser, Ayper Somer, Guside Aksu, Necil Kutukculer, Davood Mansouri, Alireza Mahdaviani, Setareh Mamishi, Alexandre Alcais, Laurent Abel, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.
  PLoS ONE 01/2011; 6(4):e18524. · 4.09 Impact Factor
• Source

  Available from: Dewton de Moraes Vasconcelos

  Article: IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

  Sophie Hambleton, Sandra Salem, B Sc, Jacinta Bustamante, Venetia Bigley, Stéphanie Boisson-Dupuis, Joana Azevedo, Anny Fortin, Muzlifah Haniffa, Lourdes Ceron-Gutierrez, [......], Anete Grumach, Alberto Duarte, Katia Abarca, Dewton Moraes-Vasconcelos, David Burk, Albert Berghuis, Frédéric Geissmann, Matthew Collin, Jean-Laurent Casanova, Philippe Gros
  N Engl J Med Copyright © Massachusetts Medical Society. 01/2011;
• Article: A novel form of human STAT1 deficiency impairing early but not late responses to interferons.

  Xiao-Fei Kong, Michael Ciancanelli, Sami Al-Hajjar, Laia Alsina, Timothy Zumwalt, Jacinta Bustamante, Jacqueline Feinberg, Magali Audry, Carolina Prando, Vanessa Bryant, Alexandra Kreins, Dusan Bogunovic, Rabih Halwani, Xin-Xin Zhang, Laurent Abel, Damien Chaussabel, Saleh Al-Muhsen, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis
  [show abstract] [hide abstract]
  ABSTRACT: Autosomal recessive STAT1 deficiency is associated with impaired cellular responses to interferons and susceptibility to intracellular bacterial and viral infections. We report here a new form of partial STAT1 deficiency in 2 siblings presenting mycobacterial and viral diseases. Both carried a homozygous missense mutation replacing a lysine with an asparagine residue at position 201 (K201N) of STAT1. This mutation causes the abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing (by ~ 70%) STAT1 protein levels. The mutant STAT1 proteins are not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into γ-activating factor and heterotrimerization into ISGF-3, binding to specific DNA elements, and activation of the transcription. Interestingly, the activation of γ-activating factor and ISGF3 was impaired only at early time points in the various cells from patient (within 1 hour of stimulation), whereas sustained impairment occurs in other known forms of complete and partial recessive STAT1 deficiency. Consequently, delayed responses were normal; however, the early induction of interferon-stimulated genes was selectively and severely impaired. Thus, the early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections.
  Blood 12/2010; 116(26):5895-906. · 9.90 Impact Factor
• Source

  Available from: Dewton de Moraes Vasconcelos

  Article: Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries.

  Ludovic de Beaucoudrey, Arina Samarina, Jacinta Bustamante, Aurélie Cobat, Stéphanie Boisson-Dupuis, Jacqueline Feinberg, Saleh Al-Muhsen, Lucile Jannière, Yoann Rose, Maylis de Suremain, [......], Nima Parvaneh, Sergio Rosenzweig, Ridha Barbouche, Sigifredo Pedraza, Yu Lung Lau, Mohammad S Ehlayel, Claire Fieschi, Laurent Abel, Ozden Sanal, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
  Medicine 11/2010; 89(6):381-402. · 4.35 Impact Factor
• Article: Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN-gamma receptor 1 deficiency.

  Carolina Prando, Stéphanie Boisson-Dupuis, Audrey V Grant, Xiao-Fei Kong, Jacinta Bustamante, Jacqueline Feinberg, Ariane Chapgier, Yoann Rose, Lucile Jannière, Elena Rizzardi, Qiuping Zhang, Catherine M Shanahan, Louis Viollet, Stanislas Lyonnet, Laurent Abel, Ezia Maria Ruga, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a 7-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD.
  American Journal of Medical Genetics Part A 02/2010; 152A(3):622-9. · 2.39 Impact Factor
• Article: A novel form of cell type-specific partial IFN-gammaR1 deficiency caused by a germ line mutation of the IFNGR1 initiation codon.

  Xiao-Fei Kong, Guillaume Vogt, Ariane Chapgier, Christophe Lamaze, Jacinta Bustamante, Carolina Prando, Anny Fortin, Anne Puel, Jacqueline Feinberg, Xin-Xin Zhang, Pauline Gonnord, Ulla M Pihkala-Saarinen, Mikko Arola, Petra Moilanen, Laurent Abel, Matti Korppi, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: IFN-gammaR1 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial diseases, and includes two forms of complete recessive deficiency, with or without cell surface expression, and two forms of partial deficiency, dominant or recessive. We report here a novel form of partial and recessive Interferon gamma receptor 1 (IFN-gammaR1) deficiency, which is almost as severe as complete deficiency. The patient is homozygous for a mutation of the initiation codon (M1K). No detectable expression and function of IFN-gammaR1 were found in the patient's fibroblasts. However, IFN-gammaR1 expression was found to be impaired, but not abolished, on the EBV-transformed B cells, which could respond weakly to IFN-gamma. The mechanism underlying this weak expression involves leaky translation initiation at both non-AUG codons and the third AUG codon at position 19. It results in the residual expression of IFN-gammaR1 protein of normal molecular weight and function. The residual IFN-gamma signaling documented in this novel form of partial IFN-gammaR1 deficiency was not ubiquitous and was milder than that seen in other forms of partial IFN-gammaR1 deficiency, accounting for the more severe clinical phenotype of the patient, which was almost as severe as that of patients with complete deficiency.
  Human Molecular Genetics 10/2009; 19(3):434-44. · 7.64 Impact Factor
• Source

  Available from: Ariane Chapgier

  Article: Disseminated Mycobacterium scrofulaceum infection in a child with interferon-gamma receptor 1 deficiency.

  Maria Grazia Marazzi, Ariane Chapgier, Anna-Carla Defilippi, Vito Pistoia, Sara Mangini, Cesarina Savioli, Anna Dell'Acqua, Jacqueline Feinberg, Enrico Tortoli, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Disseminated disease caused by non-tuberculous, environmental mycobacteria (EM) reflects impaired host immunity. Disseminated disease caused by Mycobacterium scrofulaceum has primarily been reported in patients with AIDS. Moreover, observing M. scrofulaceum as the agent of localized disease in childhood has become increasingly rare. We report the first case of disseminated disease caused by M. scrofulaceum in a child with inherited interferon-gamma receptor 1 (IFN-gammaR1) complete deficiency. As in this case, mycobacterial bone infections in IFN-gammaR1 deficiency can sometimes mimic the clinical picture of chronic recurrent multifocal osteomyelitis.
  International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 10/2009; 14(2):e167-70. · 2.17 Impact Factor
• Article: Successful hematopoietic stem cell transplantation from an unrelated donor in a child with interferon gamma receptor deficiency.

  Petra Moilanen, Matti Korppi, Liisa Hovi, Ariane Chapgier, Jacqueline Feinberg, Xiao-Fei Kong, Stéphanie Boisson-Dupuis, Mikko Arola, Jean-Laurent Casanova, Ulla M Saarinen-Pihkala
  [show abstract] [hide abstract]
  ABSTRACT: Interferon gamma receptor deficiency is a rare autosomal recessive inherited disorder, with poor prognosis due to early-onset, recurrent, and disseminated mycobacterial infections. Hematopoietic stem cell transplantation (HSCT), the only curative treatment, is particularly difficult in these patients owing to a high rate of graft rejection. We report the first successful hematopoietic stem cell transplantation with an unrelated donor, performed in a schoolgirl with severe interferon gamma receptor 1deficiency caused by a novel mutation.
  The Pediatric Infectious Disease Journal 06/2009; 28(7):658-60. · 3.58 Impact Factor
• Article: A partial form of recessive STAT1 deficiency in humans.

  Ariane Chapgier, Xiao-Fei Kong, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Diana Averbuch, Jacqueline Feinberg, Shen-Ying Zhang, Jacinta Bustamante, Guillaume Vogt, Julien Lejeune, Eleonore Mayola, Ludovic de Beaucoudrey, Laurent Abel, Dan Engelhard, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
  The Journal of clinical investigation 06/2009; 119(6):1502-14. · 15.39 Impact Factor
• Article: Simultaneous presentation of 2 rare hereditary immunodeficiencies: IL-12 receptor beta1 deficiency and ataxia-telangiectasia.

  Mohammad Ehlayel, Ludovic de Beaucoudrey, Francesca Fike, Shareef A Nahas, Jacqueline Feinberg, Jean-Laurent Casanova, Richard A Gatti
  The Journal of allergy and clinical immunology 09/2008; 122(6):1217-9. · 9.17 Impact Factor
• Source

  Available from: Ariane Chapgier

  Article: Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation.

  Guillaume Vogt, Jacinta Bustamante, Ariane Chapgier, Jacqueline Feinberg, Stephanie Boisson Dupuis, Capucine Picard, Nizar Mahlaoui, Laure Gineau, Alexandre Alcaïs, Christophe Lamaze, Jennifer M Puck, Geneviève de Saint Basile, Claudia Djambas Khayat, Raymond Mikhael, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: Germline mutations may cause human disease by various mechanisms. Missense and other in-frame mutations may be deleterious because the mutant proteins are not correctly targeted, do not function correctly, or both. We studied a child with mycobacterial disease caused by homozygosity for a novel in-frame microinsertion in IFNGR2. In cells transfected with the mutant allele, most of the interferon gamma receptor 2 (IFN-gamma R2) protein was retained within the cell, and that expressed on the cell surface had an abnormally high molecular weight (MW). The misfolding mutation was not gain-of-glycosylation, as it created no new N-glycosylation site. The mutant IFNGR2 allele was null, as the patient's cells did not respond to IFN-gamma. Based on the well-established relationship between protein N-glycosylation and protein quality control processes, we tested 29 compounds affecting maturation by N-glycosylation in the secretory pathway. Remarkably, up to 13 of these compounds reduced the MW of surface-expressed mutant IFN-gamma R2 molecules and restored cellular responsiveness to IFN-gamma. Modifiers of N-glycosylation may therefore complement human cells carrying in-frame and misfolding, but not necessarily gain-of-glycosylation, mutations in genes encoding proteins subject to trafficking via the secretory pathway. Some of these compounds are available for clinical use, paving the way for clinical trials of chemical complementation for various human genetic traits.
  Journal of Experimental Medicine 08/2008; 205(8):1729-37. · 13.85 Impact Factor
• Source

  Available from: Yvon Lebranchu

  Article: Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

  Ludovic de Beaucoudrey, Anne Puel, Orchidée Filipe-Santos, Aurélie Cobat, Pegah Ghandil, Maya Chrabieh, Jacqueline Feinberg, Horst von Bernuth, Arina Samarina, Lucile Jannière, [......], Ben-Zion Garty, Figen Dogu, Yildiz Camcioglu, Sanyie Gülle, Ozden Sanal, Alain Fischer, Laurent Abel, Birgitta Stockinger, Capucine Picard, Jean-Laurent Casanova
  [show abstract] [hide abstract]
  ABSTRACT: The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
  Journal of Experimental Medicine 08/2008; 205(7):1543-50. · 13.85 Impact Factor