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  1. Article ; Online: Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments

    Edgard Verdura / Laura Pérez-Cano / Rubén Sabido-Vera / Emre Guney / Jean-Marc Hyvelin / Lynn Durham / Baltazar Gomez-Mancilla

    Frontiers in Psychiatry, Vol

    2021  Volume 12

    Abstract: Fragile X syndrome (FXS) is the most frequent monogenic cause of autism or intellectual disability, and research on its pathogenetic mechanisms has provided important insights on this neurodevelopmental condition. Nevertheless, after 30 years of intense ... ...

    Abstract Fragile X syndrome (FXS) is the most frequent monogenic cause of autism or intellectual disability, and research on its pathogenetic mechanisms has provided important insights on this neurodevelopmental condition. Nevertheless, after 30 years of intense research, efforts to develop treatments have been mostly unsuccessful. The aim of this review is to compile evidence from existing research pointing to clinical, genetic, and therapeutic response heterogeneity in FXS and highlight the need of implementing precision medicine-based treatments. We comment on the high genetic and phenotypic heterogeneity present in FXS, as a contributing factor to the difficulties found during drug development. Given that several clinical trials have showed a non-negligeable fraction of positive responders to drugs targeting core FXS symptoms, we propose that success of clinical trials can be achieved by tackling the underlying heterogeneity in FXS by accurately stratifying patients into drug-responder subpopulations. These precision medicine-based approaches, which can be first applied to well-defined monogenic diseases such as FXS, can also serve to define drug responder profiles based on specific biomarkers or phenotypic features that can associate patients with different genetic backgrounds to a same candidate drug, thus repositioning a same drug for a larger number of patients with NDDs.
    Keywords Fragile X syndrome ; precision medicine-based treatments ; autism spectrum disorders ; biomarkers ; monogenic disease ; heterogeneity ; Psychiatry ; RC435-571
    Subject code 610
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

    Nathalie Launay / Montserrat Ruiz / Laura Planas-Serra / Edgard Verdura / Agustí Rodríguez-Palmero / Agatha Schlüter / Leire Goicoechea / Cristina Guilera / Josefina Casas / Felix Campelo / Emmanuelle Jouanguy / Jean-Laurent Casanova / Odile Boespflug-Tanguy / Maria Vazquez Cancela / Luis González Gutiérrez-Solana / Carlos Casasnovas / Estela Area-Gomez / Aurora Pujol

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 14

    Abstract: The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated ... ...

    Abstract The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid–droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.
    Keywords Metabolism ; Neuroscience ; Medicine ; R
    Subject code 572 ; 570
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: DMD Mutations in 576 Dystrophinopathy Families

    Jonas Juan-Mateu / Lidia Gonzalez-Quereda / Maria Jose Rodriguez / Manel Baena / Edgard Verdura / Andres Nascimento / Carlos Ortez / Montserrat Baiget / Pia Gallano

    PLoS ONE, Vol 10, Iss 8, p e

    A Step Forward in Genotype-Phenotype Correlations.

    2015  Volume 0135189

    Abstract: Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD) require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we ... ...

    Abstract Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD) require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we performed a comprehensive analysis of the DMD mutational spectrum in a large series of families. Here we provide the clinical, pathological and genetic features of 576 dystrophinopathy patients. DMD gene analysis was performed using the MLPA technique and whole gene sequencing in blood DNA and muscle cDNA. The impact of the DNA variants on mRNA splicing and protein functionality was evaluated by in silico analysis using computational algorithms. DMD mutations were detected in 576 unrelated dystrophinopathy families by combining the analysis of exonic copies and the analysis of small mutations. We found that 471 of these mutations were large intragenic rearrangements. Of these, 406 (70.5%) were exonic deletions, 64 (11.1%) were exonic duplications, and one was a deletion/duplication complex rearrangement (0.2%). Small mutations were identified in 105 cases (18.2%), most being nonsense/frameshift types (75.2%). Mutations in splice sites, however, were relatively frequent (20%). In total, 276 mutations were identified, 85 of which have not been previously described. The diagnostic algorithm used proved to be accurate for the molecular diagnosis of dystrophinopathies. The reading frame rule was fulfilled in 90.4% of DMD patients and in 82.4% of Becker muscular dystrophy patients (BMD), with significant differences between the mutation types. We found that 58% of DMD patients would be included in single exon-exon skipping trials, 63% from strategies directed against multiexon-skipping exons 45 to 55, and 14% from PTC therapy. A detailed analysis of missense mutations provided valuable information about their impact on the protein structure.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

    Sukhleen Kour / Deepa S. Rajan / Tyler R. Fortuna / Eric N. Anderson / Caroline Ward / Youngha Lee / Sangmoon Lee / Yong Beom Shin / Jong-Hee Chae / Murim Choi / Karine Siquier / Vincent Cantagrel / Jeanne Amiel / Elliot S. Stolerman / Sarah S. Barnett / Margot A. Cousin / Diana Castro / Kimberly McDonald / Brian Kirmse /
    Andrea H. Nemeth / Dhivyaa Rajasundaram / A. Micheil Innes / Danielle Lynch / Patrick Frosk / Abigail Collins / Melissa Gibbons / Michele Yang / Isabelle Desguerre / Nathalie Boddaert / Cyril Gitiaux / Siri Lynne Rydning / Kaja K. Selmer / Roser Urreizti / Alberto Garcia-Oguiza / Andrés Nascimento Osorio / Edgard Verdura / Aurora Pujol / Hannah R. McCurry / John E. Landers / Sameer Agnihotri / E. Corina Andriescu / Shade B. Moody / Chanika Phornphutkul / Maria J. Guillen Sacoto / Amber Begtrup / Henry Houlden / Janbernd Kirschner / David Schorling / Sabine Rudnik-Schöneborn / Tim M. Strom

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder. ...

    Abstract GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.
    Keywords Science ; Q
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes.

    Jonàs Juan-Mateu / Lidia González-Quereda / Maria José Rodríguez / Edgard Verdura / Kira Lázaro / Cristina Jou / Andrés Nascimento / Cecilia Jiménez-Mallebrera / Jaume Colomer / Soledad Monges / Fabiana Lubieniecki / Maria Eugenia Foncuberta / Samuel Ignacio Pascual-Pascual / Jesús Molano / Montserrat Baiget / Pia Gallano

    PLoS ONE, Vol 8, Iss 3, p e

    2013  Volume 59916

    Abstract: DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered ...

    Abstract DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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