Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined. Targeted deletion of Zeb2 resulted in impaired NK cell maturation, survival, and exit from the bone marrow. NK cell function was preserved, but mice lacking Zeb2 in NK cells were more susceptible to B16 melanoma lung metastases. Reciprocally, ectopic expression of Zeb2 resulted in a higher frequency of mature NK cells in all organs. Moreover, the immature phenotype of Zeb2(-/-) NK cells closely resembled that of Tbx21(-/-) NK cells. This was caused by both a dependence of Zeb2 expression on T-bet and a probable cooperation of these factors in gene regulation. Transgenic expression of Zeb2 in Tbx21(-/-) NK cells partially restored a normal maturation, establishing that timely induction of Zeb2 by T-bet is an essential event during NK cell differentiation. Finally, this novel transcriptional cascade could also operate in human as T-bet and Zeb2 are similarly regulated in mouse and human NK cells

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Couloisy (Oise) « Le Village » : la ferme censière de la Grant Maison: Rapport de fouille 2017

National audienceL’opération de fouilles préventives, menée de mai à octobre 2010, au cœur du village isarien de Couloisy (60), faisait suite au diagnostic mené en 2005 par Muriel Friboulet (Inrap) dont les résultats avaient suggéré la présence d’une occupation des lieux à l’époque mérovingienne puis au bas Moyen Âge (Friboulet, 2005). Le projet d’aménagement (zone de lotissements individuels) concernait effectivement une zone particulièrement sensible sur le plan archéologique, par sa proximité avec l’église romane paroissiale et la mention de sarcophages alentours, mal localisés au XIXe siècle. Répondant aux problématiques des occupations humaines de la vallée de l’Aisne, cette fouille donnait ainsi l’opportunité de documenter ce territoire, dans un secteur encore peu renseigné (la basse vallée, entre Soissons et la confluence Aisne-Oise au nord de Compiègne), tout en s’intégrant pleinement dans l’axe 10 de la programmation nationale de la recherche archéologique Espace rural, peuplement et productions agricoles aux époques gallo-romaine, médiévale et moderne

From one ritual to another: the long-term sequence of the Bury gallery grave (northern France, fourth–second millennia BC)

International audienceMegalithic or earth-cut chambered tombs containing large numbers of buried individuals are a key feature of the Late Neolithic of northern France. The discovery and analysis of one such tomb at Bury offers an exceptional opportunity to investigate changing burial practices during the fourth and third millennia BC. This was not a static monument: funerary practice changed significantly over time, and several different episodes of mortuary use have been identified. Comparing and contrasting these episodes suggests that there was no substantial change in the local population using the grave, but changes in burial practice reveal a shift towards more selective inclusion. These may reflect broader changes in contemporary society during the third millennium BC

Couloisy (Oise) « Le Village » : la ferme censière de la Grant Maison: Rapport de fouille 2017

National audienceL’opération de fouilles préventives, menée de mai à octobre 2010, au cœur du village isarien de Couloisy (60), faisait suite au diagnostic mené en 2005 par Muriel Friboulet (Inrap) dont les résultats avaient suggéré la présence d’une occupation des lieux à l’époque mérovingienne puis au bas Moyen Âge (Friboulet, 2005). Le projet d’aménagement (zone de lotissements individuels) concernait effectivement une zone particulièrement sensible sur le plan archéologique, par sa proximité avec l’église romane paroissiale et la mention de sarcophages alentours, mal localisés au XIXe siècle. Répondant aux problématiques des occupations humaines de la vallée de l’Aisne, cette fouille donnait ainsi l’opportunité de documenter ce territoire, dans un secteur encore peu renseigné (la basse vallée, entre Soissons et la confluence Aisne-Oise au nord de Compiègne), tout en s’intégrant pleinement dans l’axe 10 de la programmation nationale de la recherche archéologique Espace rural, peuplement et productions agricoles aux époques gallo-romaine, médiévale et moderne

Vulnerability of Douglas-fir in a changing climate: study of decline in France after the extreme 2003’s drought

International audienc

Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20

International audiencePrimrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive

Development of a new expanded next‐generation sequencing panel for genetic diseases involved in dyslipidemia

International audienceThe aim of this study was to provide an efficient tool: reliable, able to increase the molecular diagnosis performance, to facilitate the detection of copy number variants (CNV), to assess genetic risk scores (wGRS) and to offer the opportunity to explore candidate genes. Custom SeqCap EZ libraries, NextSeq500 sequencing and a homemade pipeline enable the analysis of 311 dyslipidemia-related genes. In the training group (48 DNA from patients with a well-established molecular diagnosis), this next-generation sequencing (NGS) workflow showed an analytical sensitivity >99% (n = 532 variants) without any false negative including a partial deletion of one exon. In the prospective group, from 25 DNA from patients without prior molecular analyses, 18 rare variants were identified in the first intention panel genes, allowing the diagnosis of monogenic dyslipidemia in 11 patients. In six other patients, the analysis of minor genes and wGRS determination provided a hypothesis to explain the dyslipidemia. Remaining data from the whole NGS workflow identified four patients with potentially deleterious variants. This NGS process gives a major opportunity to accede to an enhanced understanding of the genetic of dyslipidemia by simultaneous assessment of multiple genetic determinants

NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome

International audienceTelomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR, and several cofactors including the H/ACA box ribonucleoproteins (RNP) Dyskerin, NOP10, GAR1, NAF1, and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure (BMF), and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome (HH), the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Lastly, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency