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Hôpital-Camfrout, France

Richard A.,French Institute of Health and Medical Research | Corvol J.-C.,French Institute of Health and Medical Research | Tahiri K.,French Institute of Health and Medical Research | Carpentier W.,Plateforme Post genomique P3S | And 3 more authors.
Medicine (United States)

We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration=6 [0.83-6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC]>1.2, P<0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-a receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC=1.8, P=1.7E-7, FDR=0.004; p21 protein-activated kinase 2 [PAK2]: FC=1.66, P=2.6E-5, FDR=0.03; TNF-a-induced protein 8-like protein 1 [TNFAIP8L1]: P=1.00E-05, FDR=0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC=1.6, P=2E-5, FDR=0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC=1.5, P=1E-05, FDR=0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score=24, Fischer exact test=0.003). TNF-a gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P=0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity that is lessened by IVIg. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

Le Guen T.,French Institute of Health and Medical Research | Le Guen T.,University of Paris Pantheon Sorbonne | Touzot F.,French Institute of Health and Medical Research | Touzot F.,University of Paris Pantheon Sorbonne | And 22 more authors.
Journal of Allergy and Clinical Immunology

Background Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives We sought to characterize the underlying genetic cause of this syndrome. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency. © 2015 American Academy of Allergy, Asthma & Immunology. Source

Le Clerc S.,French National Conservatory of Arts and Crafts | Taing L.,French National Conservatory of Arts and Crafts | Ezzedine K.,University of Paris 13 | Latreille J.,CE.R.I.E.S. | And 17 more authors.
Journal of Investigative Dermatology

A genome-wide association study (GWAS) was conducted on 502 French middle-aged Caucasian women to identify genetic factors that may affect skin aging severity. A high-throughput Illumina Human Omni1-Quad beadchip was used. After single-nucleotide polymorphism (SNP) quality controls, 795,063 SNPs remained for analysis purposes. Possible stratification was first examined using the Eigenstrat method, and then the relationships between genotypes and four skin aging indicators (global photoaging, lentigines, wrinkles, and sagging) were investigated separately by linear regressions adjusted on age, smoking habits, lifetime sun exposure, hormonal status, and the two main Eigen vectors. One signal passed the Bonferroni threshold (P=1.53 × 10 -8) and was significantly associated with global photoaging. It was also correlated with the wrinkling score and the sagging score. According to HapMap, this SNP, rs322458, was in linkage disequilibrium (LD) with intronic SNPs of the STXBP5L gene, which is expressed in the skin. In addition, it was also in LD with another SNP that increases the expression of the FBXO40 gene in the skin. These two genes, which were not previously described in the context of aging, may constitute good candidates for the investigation of molecular mechanisms of skin photoaging. © 2013 The Society for Investigative Dermatology. Source

Bujakowska K.M.,Massachusetts Eye and Ear Infirmary | Bujakowska K.M.,Institute National dela Santeetde la Recherche Medicale U968 | Bujakowska K.M.,Paris-Sorbonne University | Bujakowska K.M.,French National Center for Scientific Research | And 41 more authors.
Human Molecular Genetics

Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog [IFT172 (Chlamydomonas)] that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy. © The Author 2014. Published by Oxford University Press. All rights reserved. Source

Bujakowska K.,French Institute of Health and Medical Research | Bujakowska K.,French National Center for Scientific Research | Bujakowska K.,University Pierre and Marie Curie | Audo I.,French Institute of Health and Medical Research | And 34 more authors.
Human Mutation

Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to rod-cone dystrophy, also called retinitis pigmentosa (RP). Moreover, retinal dystrophies resulting from CRB1 mutations may be accompanied by specific fundus features: preservation of the para-arteriolar retinal pigment epithelium (PPRPE) and retinal telangiectasia with exudation (also referred to as Coats-like vasculopathy). In this publication, we report seven novel mutations and classify over 150 reported CRB1 sequence variants that were found in more that 240 patients. The data from previous reports were used to analyze a potential correlation between CRB1 variants and the clinical features of respective patients. This meta-analysis suggests that the differential phenotype of patients with CRB1 mutations is due to additional modifying factors rather than particular mutant allele combination. © 2011 Wiley Periodicals, Inc. Source

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