María Moreno‐Igoa

Complejo Hospitalario de Navarra

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Ana Cristina Calvo

Universidad de Zaragoza

Rosario Osta

Universidad de Zaragoza

P. Zaragoza

Universidad de Zaragoza

Marı́a Jesús Muñoz

Universidad de Zaragoza

Raquel Manzano

Universidad de Zaragoza

Sara Oliván

Universidad de Zaragoza

María A. Ramos‐Arroyo

Navarrabiomed

Janne M. Toivonen

Universidad de Zaragoza

Blanca Hernández‐Charro

Complejo Hospitalario de Navarra

Alfredo Santana

Universidad de Las Palmas de Gran Canaria

Cooperative Institutions

Instituto de Salud Carlos III

Centre for Biomedical Network Research on Rare Diseases

Universidad Autónoma de Madrid

Centro de Investigación Biomédica en Red

Hospital Universitario Fundación Jiménez Díaz

Instituto de Investigación de Enfermedades Raras

Biomedical Research Networking Center on Neurodegenerative Diseases

Universidad de Zaragoza

Universidad de Navarra

Universitat Autònoma de Barcelona

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Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy

Journal of Molecular Medicine (2009)

María Moreno‐Igoa Ana Cristina Calvo Clara Penas Raquel Manzano Sara Oliván

10.1007/s00109-009-0556-y

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Citations (53)

KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome

BMC Medical Genetics (2015)

María Moreno‐Igoa Blanca Hernández‐Charro Amaya Bengoa‐Alonso Aranzazu Pérez-Juana-del-Casal Carlos Romero-Ibarra

Chromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region. Patients with KANSL1 intragenic mutations have been reported to display the major clinical features of 17q21.31 microdeletion syndrome. However, they did not exhibit the full clinical spectrum of this disorder, which might indicate that an additional gene or genes, located in the 17q21.31 locus, might also be involved in the syndrome's phenotype.Conventional and molecular karyotypes were performed on a female patient with intellectual disability, agenesis of the corpus callosum, heart defects, hydronephrosis, hypotonia, pigmentary skin anomalies and facial dysmorphic features. FISH analysis was conducted for chromosomal breakpoint localization. qRT-PCR was applied for the comparative gene expression of KANSL1 gene in the patient and a control group.Herein, we present the first report of disruption and haploinsufficiency of the KANSL1 gene, secondary to a t(1;17)(q12;q21)dn chromosomal translocation in a girl that also carried a de novo ~289-kb deletion on 16p11.2. KANSL1 gene expression studies and comparative clinical analysis of patients with 17q21.31 deletions and intragenic KANSL1 gene defects indicate that KANSL1 dysfunction is associated with the full spectrum of the 17q21.31 microdeletion syndrome, which includes characteristic facial features, hypotonia, intellectual disability, and structural defects of the brain, heart and genitourinary system, as well as, musculoskeletal and neuroectodermal anomalies. Moreover, we provide further evidence for the overlapping clinical phenotype of this condition with the cardio-facio-cutaneous (CFC) syndrome.KANSL1 gene haploinsufficiency is necessary and sufficient to cause the full spectrum of the 17q21.31 microdeletion syndrome. We hypothesize that the KANSL1 gene might have an effect on the Ras/mitogen-activated protein kinase (MAPK) pathway activity, which is known to be deregulated in the CFC syndrome. This pathway has a crucial role in the development of the heart and craniofacial morphology, as well as the skin, eye, brain and musculoskeletal systems.

Haploinsufficiency

Microdeletion syndrome

Chromosomal region

Comparative genomic hybridization

10.1186/s12881-015-0211-0

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Citations (33)

Lack of a synergistic effect of a non-viral ALS gene therapy based on BDNF and a TTC fusion molecule

Orphanet Journal of Rare Diseases (2011)

Ana Cristina Calvo María Moreno‐Igoa Renzo Mancuso Raquel Manzano Sara Oliván

Abstract Background Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. Neurotrophic factors have been widely tested to counteract neurodegenerative conditions, despite their unspecific neuronal access. The non-toxic C-terminal fragment of the tetanus toxin (TTC) heavy chain has been studied not only as a carrier molecule to the CNS but also as a neuroprotective agent. Because the neurotrophic effects of BDNF have been demonstrated in vitro and in vivo , the question addressed in this work is whether a fusion molecule of BDNF-TTC may have a synergistic effect and enhance the neuroprotective properties of TTC alone in a mouse model of ALS. Methods Recombinant plasmid constructs (pCMV-TTC and pCMV-BDNF-TTC) were injected into the quadriceps femoris and triceps brachialis muscles of SOD1 G93A transgenic mice at 8 weeks of age. The hanging wire and rotarod tests were performed to assess motor coordination, strength and balance. Electrophysiological tests, morphological assays of spinal cord sections of L2 and L4 segments, and gene and protein expression analyses were performed. The Kaplan-Meier survival analysis test was used for comparisons of survival. Multiple comparisons of data were analyzed using a one-way analysis of variance (ANOVA). Results Treatment with the fusion-molecule BDNF-TTC and with TTC alone significantly delayed the onset of symptoms and functional deficits of SOD1 G93A mice. Muscle innervation was partially preserved with these treatments, and the number of surviving motoneurons in L2 spinal cord segment was increased particularly by the fusion protein induction. Inhibition of pro-apoptotic protein targets (caspase-3 and Bax) and significant phosphorylation of Akt and ERK were also found in the spinal cord of treated mice. Conclusions Significant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival-activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effects.

10.1186/1750-1172-6-10

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Citations (36)

NGS mapped breakpoints in balanced chromosomal rearrangements including the first large cohort of healthy carriers

Molecular Cytogenetics (2017)

Niels Tommerup Ana Carolina S. Fonseca Mana M. Mehrjouy Malene B. Rasmussen Iben Bache

Human genetics

Breakpoint

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Effects of gene therapy on muscle 18S rRNA expression in mouse model of ALS

BMC Research Notes (2010)

María Moreno‐Igoa Raquel Manzano Sara Oliván Ana Cristina Calvo Janne M. Toivonen

The efficiency of gene therapy experiments is frequently evaluated by measuring the impact of the treatment on the expression of genes of interest by quantitative real time PCR (qRT-PCR) and by normalizing these values to those of housekeeping (HK) genes constitutively expressed throughout the experiment. The objective of this work was to study the effects of muscle gene therapy on the expression of 18 S ribosomal RNA (Rn18S), a commonly used HK gene.Mouse model of motor neuron disease (SOD1-G93A) was injected intramuscularly with Brain-derived neurotrophic factor (BDNF-TTC) encoding or control naked DNA plasmids. qRT-PCR expression analysis was performed for BDNF and HK genes Rn18 S, glyceraldehyde-3-phosphate dehydrogenase (Gapdh) and β-actin (Actb). We report that elevated BDNF expression in the injected muscle was accompanied with increased Rn18 S expression, whereas Gapdh and Actb were not affected. Increased "ribosomal output" upon BDNF stimulation was supported by increased steady-state levels of ribosomal protein mRNAs.Ribosomal RNA transcription may be directly stimulated by administration of trophic factors. Caution should be taken in using Rn18 S as a HK gene in experiments where muscle metabolism is likely to be altered by therapeutic intervention.

Housekeeping gene

Glyceraldehyde 3-phosphate dehydrogenase

Ribosomal protein

10.1186/1756-0500-3-275

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Citations (5)

Supplementary Material for: Altered Expression of Myogenic Regulatory Factors in the Mouse Model of Amyotrophic Lateral Sclerosis

Figshare (2011)

Raquel Manzano Janne M. Toivonen Sara Oliván Ana Cristina Calvo María Moreno‐Igoa

Background: In the superoxide dismutase 1 (SOD1)-G93A mouse model of amyotrophic lateral sclerosis (ALS), skeletal muscle is a key target of mutant SOD1 toxicity. However, the expression of factors that control the regenerative potential of the muscle is unknown in this model. Objective: To characterize the expression of satellite cell marker Pax7 and myogenic regulatory factors (MRF) in skeletal muscle of SOD1-G93A mice at different stages of the disease. Methods: The expressions of Pax7, Myod1, Myf5 and myogenin (Myog) were determined by quantitative real-time PCR and by Western blotting from the grouped gastrocnemius, quadriceps and soleus muscles of SOD1-G93A mice at presymptomatic, symptomatic and terminal stages of the disease, and from surgically denervated wild-type gastrocnemius muscles. Results:Pax7 mRNA and MYF5 protein were upregulated in presymptomatic mice, coinciding with increased muscle damage marker Rrad and chemokine Ccl5. All MRF transcripts and most proteins (excluding MYOG) were increased, starting from 3 months of age, simultaneously with increased expression of denervation marker Chrna1. However, in the terminal stage, no protein increase was evident for Pax7 or any of the MRF despite the increased mRNA levels. The transcripts for chemokine Ccl2 and chemokine receptor Cxcr4 were increased starting from the onset of symptoms. Conclusions: The characterization of Pax7 and MRF in SOD1-G93A mice reveals a progressive induction of the myogenic program at the RNA level, but a blunted protein level response at late stages of the disease. Altered posttranscriptional and posttranslational mechanisms likely to operate, as well as the potential role of chemokine signaling in mutant SOD1 muscle, are discussed.

Expression (computer science)

10.6084/m9.figshare.5121703

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Citations (0)

Author Correction: Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Scientific Reports (2021)

Irene Perea‐Romero Gema Gordo Ionut-Florin Iancu Marta Del Pozo‐Valero Berta Almoguera

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genetic epidemiology

10.1038/s41598-021-89275-4

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Citations (10)

Non-viral gene delivery of the GDNF, either alone or fused to the C-fragment of tetanus toxin protein, prolongs survival in a mouse ALS model

Restorative Neurology and Neuroscience (2012)

María Moreno‐Igoa Ana Cristina Calvo Jesús Ciriza Marı́a Jesús Muñoz P. Zaragoza

Purpose and background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease with no effective therapy. Glial-cell line derived neurotrophic factor (GDNF) has been translated to clinical trials for treatment of ALS an

10.3233/rnn-2011-0621

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Citations (27)

Delineation of a recognizable phenotype for the recurrent LCR22‐C to D/E atypical 22q11.2 deletion

American Journal of Medical Genetics Part A (2016)

Amaya Bengoa‐Alonso Mercè Artigas‐López María Moreno‐Igoa Claudio Cattalli Blanca Hernández‐Charro

The 22q11.2 deletion syndrome is typically caused by haploinsufficiency of a 3 Mb region that extends from LCR22‐A until LCR22‐D, while the recurrent recombination between any of the LCR22‐D to H causes the 22q11.2 distal deletion syndrome. Here, we describe three patients with a de novo atypical ∼1.4 Mb 22q11.2 deletion that involves LCR22‐C to a region beyond D (LCR22‐C to D/E), encompassing the distal portion of the typical deleted region and the proximal portion of the distal deletion. We also review six previous published patients with the same rearrangement and compare their features with those found in patients with overlapping deletions. Patients with LCR22‐C to D/E deletion present a recognizable phenotype characterized by facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay. Genotype–phenotype analysis of the patients indicates that CRKL and MAPK1 genes play an important role as causative factors for the main clinical features of the syndrome. In particular, CRKL gene seems to be involved in the occurrence of conotruncal cardiac anomalies, mainly tetralogy of Fallot. © 2016 Wiley Periodicals, Inc.

Haploinsufficiency

Microcephaly

Deletion syndrome

10.1002/ajmg.a.37614

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Citations (11)

A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model

Restorative Neurology and Neuroscience (2008)

Jesús Ciriza María Moreno‐Igoa Ana Cristina Calvo G. Yagüe José Pérez del Palacio

Amyotrophic Lateral Sclerosis (ALS) is a paralyzing disorder that kills individuals within three to five years of onset without any possibility for effective treatment. One proposed therapy has been the use of neurotrophic factors to inhibit the apoptosis of motorneurones. At the present, one way to deliver neurotrophic factors after intramuscular injection to the motor neurones is through the use of adenoviral vectors. An alternative strategy is the use of the atoxic C fragment of tetanus toxin (TTC) as a neurotrophic factor carrier for motorneurones.We have produced the recombinant protein fusion Glial Derived Neurotrophic Factor and C fragment of tetanus toxin (GDNF-TTC) and we have tested its antiapoptotic activity in degeneration culture cells and in the symptomatic SOD;{G93A} transgenic animal model for ALS.We demonstrated that GDNF-TTC induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and~maintains its antiapoptotic neuronal activity in Neuro2A cells. Moreover, we have found that genetic fusion is able to increase survival by 9 days and improves life quality in symptomatic ALS animal models.These results suggest that recombinant GDNF-TTC fusion protein intramuscular injections provide a potential therapy for ALS treatment.

10.3233/rnn-2008-00428

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Citations (42)