Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.
ISSN: 1553-7390

hal-01063929
https://hal.archives-ouvertes.fr/hal-01063929
DOI : 10.1371/journal.pgen.1004340
PUBMED : 24784881

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Two genome-wide association studies (GWASs) recently highlighted the HLA-DRA and HLA-DRB5 genes as associated with Parkinson disease (PD). However, because HLA-DRA displays a low level of polymorphisms and HLA-DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA-DR region; (2) to identify PD-associated HLA alleles; and (3) to perform a meta-analysis of our top finding. As part of 2 French population-based case-control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single-nucleotide polymorphisms (SNPs) in the HLA-DR region. HLA-DRB1 alleles were imputed using the HLA(*) IMP software. HLA typing was performed in a subsample of the participants. We performed a meta-analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57-0.87) within the HLA-DRB1 gene, which encodes the most polymorphic HLA-DR chain (DRβ). A meta-analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82-0.91; P < .0001). SNP-based imputation of HLA alleles showed an inverse association between PD and the HLA-DRB1(*) 04 allele. We replicated an association between PD and the HLA-DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA-DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. © 2012 Movement Disorder Society.
ISSN: 0885-3185

inserm-00721562
http://www.hal.inserm.fr/inserm-00721562
http://www.hal.inserm.fr/inserm-00721562/document
http://www.hal.inserm.fr/inserm-00721562/file/Table1.pdf
http://www.hal.inserm.fr/inserm-00721562/file/Table2.pdf

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 eLife Sciences Publication
Résumé : International audience
Larval recruitment, the transition of pelagic larvae into reef-associated juveniles, is a critical step for the resilience of marine fish populations but its molecular control is unknown. Here, we investigate whether thyroid-hormones (TH) and their receptors (TR) coordinate the larval recruitment of the coral-reef-fish Acanthurus triostegus. We demonstrate an increase of TH-levels and TR-expressions in pelagic-larvae, followed by a decrease in recruiting juveniles. We generalize these observations in four other coral reef-fish species. Treatments with TH or TR-antagonist, as well as relocation to the open-ocean, disturb A. triostegus larvae transformation and grazing activity. Likewise, chlorpyrifos, a pesticide often encountered in coral-reefs, impairs A. triostegus TH-levels, transformation, and grazing activity, hence diminishing this herbivore’s ability to control the spread of reef-algae. Larval recruitment therefore corresponds to a TH-controlled metamorphosis, sensitive to endocrine disruption. This provides a framework to understand how larval recruitment, critical to reef-ecosystems maintenance, is altered by anthropogenic stressors.
ISSN: 2050-084X

Droits : http://creativecommons.org/licenses/by/
hal-01633712
http://hal.upmc.fr/hal-01633712
http://hal.upmc.fr/hal-01633712/document
http://hal.upmc.fr/hal-01633712/file/elife-27595-v1.pdf
DOI : 10.7554/eLife.27595

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. METHODS: The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. RESULTS: Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. CONCLUSION: In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.
ISSN: 0305-7453

hal-00875092
https://hal.archives-ouvertes.fr/hal-00875092
DOI : 10.1093/jac/dkt033
PUBMED : 23404192