Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
ISSN: 1098-3600

hal-01134364
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01134364
DOI : 10.1038/gim.2015.29
PUBMED : 25790162

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Background: HCV treatment uptake has drastically increased in HIV-HCV coinfected patients in France since direct-acting antiviral (DAA) treatment approval, resulting in HCV cure in 63% of all HIV-HCV patients by the end of 2015. We investigated the impact of scaling-up DAA on HCV prevalence in the whole HIV population and in various risk groups over the next 10 years in France using a transmission dynamic compartmental model.Methods: The model was based on epidemiological data from the French Dat’AIDS cohort. Eight risk groups wereconsidered, including high-risk (HR) and low-risk (LR) men who have sex with men (MSM) and male/female heterosexuals,intra-venous drug users, or patients from other risk groups. The model was calibrated on prevalence and incidence dataobserved in the cohort between 2012 and 2015.Results: On January 1, 2016, 156,811 patients were registered as infected with HIV in France (24,900 undiagnosedpatients) of whom 7938 (5.1%) had detectable HCV-RNA (722 undiagnosed patients). Assuming a treatmentcoverage (TC) rate of 30%/year (i.e., the observed rate in 2015), model projections showed that HCV prevalenceamong HIV patients is expected to drop to 0.81% in 2026. Sub-analyses showed a similar decrease of HIV-HCVprevalence in most risk groups, including LR MSM. Due to higher infection and reinfection rates, predicted prevalencein HR MSM remained stable from 6.96% in 2016 to 6.34% in 2026. Increasing annual TC rate in HR MSM to 50/70%would decrease HCV prevalence in this group to 2.35/1.25% in 2026. With a 30% TC rate, undiagnosed patients wouldaccount for 34% of HCV infections in 2026.Conclusions: Our model suggests that DAA could nearly eliminate coinfection in France within 10 years for most riskgroups, including LR MSM. Elimination in HR MSM will require increased TC.
ISSN: 1741-7015

Droits : info:eu-repo/semantics/OpenAccess
inserm-01685739
http://www.hal.inserm.fr/inserm-01685739
http://www.hal.inserm.fr/inserm-01685739/document
http://www.hal.inserm.fr/inserm-01685739/file/2017%2C%20Virlogeux%20-%20Modeling%20HIV-HCV%20coinfection.pdf
DOI : 10.1186/s12916-017-0979-1

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Cytomegalovirus (CMV) infection is common among HIV-infected patients but its repercussion on the course of CD4+ and CD8+ T cells after cART initiation remains elusive. The French Dat'AIDS cohort enrolled 5,688 patients on first-line cART, from which we selected patients who achieved HIV suppression for at least 12 months without modification of cART, and for whom CMV serostatus was available. Five hundred and three patients fulfilled the selection criteria (74% male, median age 43 yrs, 15.5% CDC stage C), of whom 444 (88.3%) were seropositive for CMV (CMV+). Multivariate analyses using mixed-linear models adjusted for the time from HIV suppression, sex, age, transmission risk group, duration of HIV follow-up, the interaction between time from HIV suppression and CMV+ serol-ogy, and the nadir CD4 count revealed a negative correlation between CMV+ and CD4: CD8 ratio (coeff. =-0.16; p = 0.001). This correlation was also observed among patients displaying optimal CD4 recovery (!500 cells/mm3 at M12; coeff. =-0.24; p = 0.002). Hence, CMV+ serostatus antagonizes normalization of the CD4:CD8 ratio, although further analyses of the impact of co-morbidities that associate with CMV serostatus, like HCV infection, are needed to elucidate this antagonism formally. However, this might reflect a premature T cell senescence, thus advocating for a close monitoring of T cells in CMV co-infected patients. In addition, our results raise the question of the benefit of treatment for asymptomatic CMV co-infection in HIV-infected patients.
ISSN: 1932-6203

inserm-01418700
http://www.hal.inserm.fr/inserm-01418700
http://www.hal.inserm.fr/inserm-01418700/document
http://www.hal.inserm.fr/inserm-01418700/file/journal.pone.0165774.PDF
DOI : 10.1371/journal.pone.0165774

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
CYLD is a tumour suppressor gene mutated in familial cylindromatosis, a genetic disorder leading to the development of skin appendage tumours. It encodes a deubiquitinating enzyme that removes Lys63- or linear-linked ubiquitin chains. CYLD was shown to regulate cell proliferation, cell survival and inflammatory responses, through various signalling pathways. Here we show that CYLD localizes at centrosomes and basal bodies via interaction with the centrosomal protein CAP350 and demonstrate that CYLD must be both at the centrosome and catalytically active to promote ciliogenesis independently of NF-κB. In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking. These results point to an undiscovered regulation of ciliogenesis by Lys63 ubiquitination and provide new perspectives regarding CYLD function that should be considered in the context of cylindromatosis.
ISSN: 2041-1723

hal-01063915
https://hal.archives-ouvertes.fr/hal-01063915
DOI : 10.1038/ncomms5585
PUBMED : 25134987