Philippe Duquesnoy - Academia.edu (original) (raw)

Papers by Philippe Duquesnoy

British Journal of Haematology, 1997

Systemic mast cell disease (SMCD) is a disorder characterized by a mast cell proliferation in var... more Systemic mast cell disease (SMCD) is a disorder characterized by a mast cell proliferation in various tissues. Mast cells express the c-kit proto-oncogene. A few cases of c-kit mutations have been described in SMCD. We report an aggressive SMCD in a patient who presented with a bone marrow infiltration by abnormal mast cells. Molecular studies of mast cell DNA and RNA revealed a new c-kit heterozygous mutation (Asp820Gly). This mutation leads to a drastic amino-acid change and is located close to the highly oncogenic Asp816Val. These findings suggest that the Asp820Gly has a potential role in c-kit activation.

Current Drug Target -Inflammation & Allergy, 2005

Amyloidosis remains currently a severe potential complication of many chronic inflammatory disord... more Amyloidosis remains currently a severe potential complication of many chronic inflammatory disorders. It is not exactly know why some patients develop a progressive amyloidosis, whereas others do not although latent deposits may be present. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Among persistent or emerging causes of AA amyloidosis, hereditary periodic fever syndromes also known as auto-inflammatory syndromes are a group of diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases. Amyloid was first described in the nineteenth century as an extracellular material found in tissues of patients affected with chronic infectious diseases [1]. Amyloid has then been observed in various clinical settings leading to a first clinical classification of amyloidoses, which are the diseases associated with amyloid deposits. Four main entities were thus recognized: primary amyloidosis (i.e. amyloidosis without any detectable infectious cause, secondary amyloidosis (to an infectious disease), hereditary and localized types. A dramatic change in our knowledge of amyloid occurred in 1971, when Glenner showed that the main protein constituent of amyloid in primary amyloidosis was derived from a light

Arthritis & Rheumatism, 2011

Objective. A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD... more Objective. A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1␤ (IL-1␤) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1␤ and 3 IL-1␤-induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor ␣ [TNF␣]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders. Methods. Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment. Results. Spontaneous secretion of IL-1␤ by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1␤ secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNF␣ secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1␤ secretion. Anakinra was discontinued after 14 months of therapy. Conclusion. Our findings provide in vivo evidence of the crucial role of IL-1␤ in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.

Journal of Endocrinological Investigation, 1998

The growth hormone (GH) receptor, a member of the cytokine receptor superfamily which gives rise ... more The growth hormone (GH) receptor, a member of the cytokine receptor superfamily which gives rise to a soluble and circulating counterpart, GH binding protein (GHBP), is the main target of Laron syndrome, a severe autosomal recessive dwarfism characterized by complete GH insensibility. Genetic and mutational analyses have attested to the high molecular heterogeneity of this syndrome, and, to date, more than 30 different GH receptor mutations including deletion, frameshift, nonsense, missense and splicing defects have been described. Study of the recently described forms of atypical GH-insensitive conditions is very promising. Affected patients display detectable plasma GH binding activity associated with complete or partial GH insensitivity. Molecular analysis of one of these disease phenotypes with positive GHBP and complete GH insensitivity has revealed the existence of a missense mutation abolishing receptor homodimerization, thereby providing in vivo evidence for the critical rol...

European Respiratory Journal, 2020

IntroductionInterstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2... more IntroductionInterstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.MethodsThe consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.ResultsFor the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of...

PloS one, 2017

Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and ... more Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and Leucine-rich Repeat containing protein), which regulate the secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines. Monocytes and macrophages, the main cells expressing the inflammasome genes, adapt to their surrounding microenvironment by a phenotypic polarization towards a pro-inflammatory M1 phenotype that promotes inflammation or an anti-inflammatory M2 phenotype important for resolution of inflammation. Despite the importance of inflammasomes in health and disease, little is known about inflammasome gene expression in relevant human cells and the impact of monocyte and macrophage polarization in inflammasome gene expression. We examined the expression of several members of the NLR, caspase and cytokine family, and we studied the activation of the well-described NLRP3 inflammasome in an experimental model of polarized human primary monocytes and monocyte-derived ma...

Nature communications, Feb 8, 2017

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucoc... more By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset o...

Human molecular genetics, Jan 26, 2015

POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in th... more POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cof...

Nouvelle revue française d'hématologie

ABSTRACT

Acta paediatrica (Oslo, Norway : 1992). Supplement, 1992

Arthritis & Rheumatology, 2014

ObjectiveAutoinflammatory disorders are caused by a primary dysfunction of the innate immune syst... more ObjectiveAutoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease‐causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers.MethodsCopy number variations and point mutations were sought by array‐comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF‐κB signaling in cells expressing wild‐type and mutated forms of the receptor was evaluated by luciferase assay.ResultsA patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygo...

Proceedings of the National Academy of Sciences, 2007

Thioredoxins belong to a large family of enzymatic proteins that function as general protein disu... more Thioredoxins belong to a large family of enzymatic proteins that function as general protein disulfide reductases, therefore participating in several cellular processes via redox-mediated reactions. So far, none of the 18 members of this family has been involved in human pathology. Here we identified TXNDC3 , which encodes a thioredoxin–nucleoside diphosphate kinase, as a gene implicated in primary ciliary dyskinesia (PCD), a genetic condition characterized by chronic respiratory tract infections, left–right asymmetry randomization, and male infertility. We show that the disease, which segregates as a recessive trait, results from the unusual combination of the following two transallelic defects: a nonsense mutation and a common intronic variant found in 1% of control chromosomes. This variant affects the ratio of two physiological TXNDC3 transcripts: the full-length isoform and a novel isoform, TXNDC3d7 , carrying an in-frame deletion of exon 7. In vivo and in vitro expression data...

Pediatric Research, 1994

An Italian family with three children presenting with isolated growth hormone (GH) deficiency typ... more An Italian family with three children presenting with isolated growth hormone (GH) deficiency type IA is described. Restriction endonuclease analysis revealed that the cause of hGH deficiency was a 45-kb gene deletion within the hGH-chorionic somatomammotropin (CS) gene cluster, encompassing the GH-1, CS-L, CS-A, and GH-2 genes. DNA sequence analysis and polymerase chain reaction amplification between two sequences located on each side of the deletion breakpoint accurately identified the deletion breakpoints and indicated that the regulatory sequences located upstream from the TATA box of the mutant CS-B belong to the GH-2 gene. Two of the affected children developed high-titer anti-hGH antibodies after recombinant hGH treatment with secondary growth arrest, hGH deficiency has a prevalence ranging from 1 in 4 000 to 1 in 15 000, and 5-30% of cases are estimated to be familial (1, 2). Several single-gene disorders have been shown to result in IGHD with three different modes of inheritance: autosomal recessive (type I), autosomal dominant (type 11), and sex linked (type 111) (3). Among type I patients, Illig et al. (4) described a subgroup referred to as IGHD type IA distinguished by the following characteristics: short body length at birth, early growth retardation leading to extreme dwarfism in adulthood, typical facies, strong anabolic response during an initial course of GH rapidly followed by the appearance of anti-hGH antibodies with growth arrest. The hGH gene locus expanded during evolution into a cluster of five linked genes located on the long arm of

Journal of Medical Genetics, 2004

Human Molecular Genetics, 2000

Mutations in MEFV, a gene encoding a protein (marenostrin/pyrin) of unknown function, are associa... more Mutations in MEFV, a gene encoding a protein (marenostrin/pyrin) of unknown function, are associated with familial Mediterranean fever, a genetic condition characterized by febrile episodes of serosal inflammation. Based on its primary structure, this 781 residue protein is thought to function as a nuclear effector molecule. However, recent transient expression studies indicated a perinuclear cytoplasmic localization. Here, we describe the isolation and expression of a novel human MEFV isoform, MEFV-d2, generated by in-frame alternative splicing of exon 2. This transcript, expressed in leukocytes, predicts a 570 residue protein designated marenostrin-d2. To investigate differences in subcellular localization between the full-length protein (marenostrin-fl) and marenostrin-d2, while providing against the overexpression of transiently expressed proteins, we have generated CHO cell lines stably expressing these two isoforms fused to the green fluorescent protein. The localization pattern of marenostrin-d2 differs dramatically from that of marenostrin-fl. Marenostrin-fl is homogeneously distributed over the entire cytoplasm, whereas marenostrin-d2 concentrates into the nucleus. To map the critical domain(s) specifying these differences, deletion mutants have been generated. Deletion of the putative nuclear localization signals (NLS) does not alter the nuclear localization of marenostrin-d2 whereas, despite the lack of discernible NLS in the domain encoded by the exon 1-exon 3 splice junction, deletion of this domain indeed disrupts this localization. These data, which challenge the current domain organization model of marenostrin, strongly suggest that MEFV encodes a nuclear protein and raises the possibility that MEFV alternative splicing may control functions of wild-type and mutant marenostrin proteins by regulating their translocation to the nucleus.