Regulation of the zebrafish goosecoid promoter by mesoderm inducing factors and Xwnt1

Goosecoid is a homeobox gene that is expressed as an immediate early response to mesoderm induction by activin. We have investigated the induction of the zebrafish goosecoid promoter by the mesoderm inducing factors activin and basic fibroblast growth factor (bFGF) in dissociated zebrafish blastula cells, as well as by different wnts in intact embryos. Activin induces promoter activity, while bFGF shows a cooperative effect with activin. We have identified two enhancer elements that are functional in the induction of the goosecoid promoter. A distal element confers activin responsiveness to a heterologous promoter in the absence of de novo protein synthesis, whereas a proximal element responds only to a combination of activin and bFGE Deletion experiments show that both elements are important for full induction by activin. Nuclear proteins that bind to these elements are expressed in blastula embryos, and competition experiments show that an octamer site in the activin responsive distal element is specifically bound, suggesting a role for an octamer binding factor in the regulation of goosecoid expression by activin. Experiments in intact embryos reveal that the proximal element contains sequences that respond to Xwnt1, but not to Xwnt5c. Furthermore, we show that the distal element is active in a confined dorsal domain in embryos and responds to overexpression of activin in vivo, as well as to dorsalization by lithium. The distal element is to our knowledge the first enhancer element identified that mediates the induction of a mesodermal gene by activin

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from diferent ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), fve of which are novel including a deletion spanning the 5′ untranslated region and the frst coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identifed in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the frst MFRP genomic rearrangement, ofering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO

The phenotype of floating-harbor syndrome:clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background\ud Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.\ud \ud Methods and results\ud Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations.\ud \ud Conclusions\ud This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.The authors would like to thank the families for their cooperation and permission to publish these findings. SdM would like to thank Barto Otten. Funding was provided by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049), by Genome Québec and Genome British Columbia, and the Manton Center for Orphan Disease Research at Children’s Hospital Boston. KMB is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics. AD is supported by NIH grant K23HD073351. BBAdV and HGB were financially supported by the AnEUploidy project (LSHG-CT-2006-37627). This work was selected for study by the FORGE Canada Steering Committee, which consists of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Université de Montréal), and S. Scherer (University of Toronto). We thank the Galliera Genetic Bank - “Telethon Genetic Biobank Network” supported by Italian Telethon grants (project no. GTB07001) for providing us with specimens

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features

Encres anciennes: utilisation non conventionnelle d'aliments

peer reviewedDe tout temps l’homme utilise des pigments pour peindre. Il y a 27.000 ans déjà, près de Marseille, dans la grotte Cosquer, des fresques furent peintes par des hommes préhistoriques. Il existe deux grandes catégories de pigments et colorants: les naturels et les artificiels. La première catégories contient les pigments minéraux tels que les argiles (ocre jaune ou rouge, argile verte ou brune) mais aussi des pierres (lapis lazuli (bleu)) et les pigments organiques d’origine végétale (gaude (jaune)) ou d’origine animale (murex (pourpre). La deuxième catégorie contient les pigments et colorants artificiels issus de réactions chimiques (minium (orange)) ou bien des mi-végétaux, mi-minéraux comme les encres ferro-galliques classés dans les divers. Après avoir servi pendant plusieurs siècles, tous ces pigments ont été remplacés à la fin du XIXe par des colorants synthétiques issus de la pétrochimie, car ces derniers ont l'avantage de la reproductibilité constante des couleurs. Mais la fin programmée du pétrole suscite un regain d'intérêt pour les préparations naturelles. C'est donc très logiquement que notre laboratoire a décidé de s'intéresser au sujet et en particulier aux encres venant du jus de chou rouge et aux encres ferro-grenadiques en collaboration avec l'Abbaye de Villers-la-Ville

Encres anciennes: l'encre ferro-gallique

L'abstract ainsi que le poster peuvent être obtenus sur demande.<BR>Le poster peut être obtenu sur https://www.researchgate.net/profile/Gilles_Olive/contributions/?ev=prf_act ou bien sur http://orbi.ulg.ac.be/browse?type=authorulg&rpp=20&value=Olive%2C+Gilles+p079922International audienceLes pigments naturels sont connus et utilisés depuis des milliers d'années. En effet, les hommes préhistoriques les employaient déjà pour peindre des fresques dans les grottes qui les abritaient. Un exemple des plus parlant est la grotte Cosquer (-19.000 à -27.000 ans) située à proximité de Marseille. Les pigments et colorants peuvent être classés en deux grandes catégories: les pigments et colorants naturels et les pigments et colorants dits artificiels. Ces catégories se subdivisent elles-mêmes en cinq familles. La première de ces cinq familles regroupent les pigments minéraux parmi lesquels nous retrouvons les argiles (ocre jaune, ocre rouge, argile verte, argile brune mais aussi des pierres telles que les lapis lazuli ou la malachite). Les deuxième et troisième famille, quant à elles, rassemblent les pigments et colorants organiques, c'est-à-dire l'indigo (bleu), la gaude (jaune) et la garance (rouge) tous trois d'origine végétale (famille 2) mais aussi la cochenille domestique (rouge) ou le kermès des teinturiers (rouge carmin) d'origine animale (famille 3). Les deux dernières familles concernent les pigments et colorants artificiels. L'une d'entre elle regroupe ceux qui sont issus des réactions chimiques tels que le vert de gris et le minium. La seconde classe les divers tels que les encres de type ferro-gallique, mi-végétale mi-minérale. Tous ces pigments, bien qu'ayant été utilisés durant des siècles, ont été remplacés par des colorants de synthèse issus de l'industrie pétrolière. En effet, ils ont l'avantage de la reproductibilité dans la préparation contrairement aux pigments naturels. Mais la raréfaction du pétrole provoque un regain d'intérêt pour les préparations naturelles. C'est donc très logiquement que notre laboratoire a décidé de s'intéresser au sujet et en particulier aux encres ferro-galliques en collaboration avec l'Abbaye de Villers-la-Ville.<BR>*** L'abstract ainsi que le poster peuvent être obtenus sur demande. ***<BR>Le poster peut être obtenu sur https://www.researchgate.net/profile/Gilles_Olive/contributions/?ev=prf_act ou bien sur http://orbi.ulg.ac.be/browse?type=authorulg&rpp=20&value=Olive%2C+Gilles+p07992