Papers by Claudia Compagnucci
Understanding the pathogenetic mechanisms underlying altered neuronal function associated with CAMK2B mutations
Neuroscience & Biobehavioral Reviews, Sep 1, 2023
Author response: Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing
International Journal of Molecular Sciences, Dec 20, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Epilepsia, Jan 14, 2016
PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by f... more PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X-linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by realtime polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19-related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.
Scientific Reports, Apr 6, 2017
Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized... more Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown-Vialetto-Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell-selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy-lysosome pathway, we observed a reduced autophagic/ mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVLassociated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies. Riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine; vitamin B2) is a water-soluble group B vitamin and the precursor of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) 1. They are essential cofactors in different metabolic processes, including carbohydrate, amino acid, and lipid metabolism and the electron transport chain 2. Riboflavin cannot be readily synthesized in mammalian cells, so it must be absorbed from the diet via riboflavin transporters (RFVTs) 3-5. RFVT1 and RFVT3 are predominantly expressed in the intestine and RFVT2 in the brain. The absence of riboflavin in the diet causes a range of developmental and growth disorders 6. Furthermore, riboflavin supplementation is useful in the treatment of inborn errors of metabolism, such as mild multiple acyl-CoA dehydrogenation defect (MADD) and some mitochondrial diseases 7,8. In 2010, it was established that autosomal recessive mutations in the riboflavin transporter genes SLC52A2 (coding for RFT3, RFVT2) and SLC52A3 (alias C20orf54, coding for RFT2, RFVT3) are responsible for the neurodegenerative disorder previously identified as Brown-Vialetto-Van Laere (BVVL) or Fazio Londe (FL) syndrome 9-14. RFVT1 does not seem to be associated with a human disease (or as an alternative lethal at embryonic stage), as no patients with this deficiency have been described.
International Journal of Molecular Sciences, Oct 7, 2020
Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, su... more Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q 10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca 2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.
International Journal of Molecular Sciences, Mar 23, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Research Square (Research Square), Jun 29, 2023
Ribo avin Transporter De ciency (RTD) is a rare genetic, childhood-onset disease. This pathology ... more Ribo avin Transporter De ciency (RTD) is a rare genetic, childhood-onset disease. This pathology has a relevant neurological involvement, being characterized by motor symptoms, ponto-bulbar paralysis and sensorineural deafness. Such clinical presentation is associated with muscle weakness and motor neuron (MN) degeneration, so that RTD is considered part of the MN disease spectrum. Based on previous ndings demonstrating energy dysmetabolism and mitochondrial impairment in RTD induced Pluripotent Stem cells (iPSCs) and iPSC-derived MNs, here we address the involvement of intrinsic apoptotic pathways in disease pathogenesis using these patient-speci c in vitro models by combined ultrastructural and confocal analyses. We show impaired neuronal survival of RTD iPSCs and MNs. Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) documents severe alterations in patients' cells, including deranged mitochondrial ultrastructure, and altered plasma membrane and nuclear organization. Occurrence of aberrantly activated apoptosis is con rmed by immuno uorescence and TUNEL assays. Overall, our work provides evidence of a role played by mitochondrial dysfunction in RTD, and identi es neuronal apoptosis as a contributing event in disease pathogenesis, indicating intrinsic apoptosis pathways as possible relevant targets for more effective therapeutical approaches.
Evolution & Development, Nov 1, 2011
the Hinge and Caps model and provide evidence that Satb2 regulates coordinated distal jaw modules... more the Hinge and Caps model and provide evidence that Satb2 regulates coordinated distal jaw modules that are subject to evolutionary modification by signals emanating from the Hinge.
Left-right asymmetry of the gnathostome skull: Its evolutionary, developmental, and functional aspects
Genesis, May 8, 2014
SummaryMuch of the gnathostome (jawed vertebrate) evolutionary radiation was dependent on the abi... more SummaryMuch of the gnathostome (jawed vertebrate) evolutionary radiation was dependent on the ability to sense and interpret the environment and subsequently act upon this information through utilization of a specialized mode of feeding involving the jaws. While the gnathostome skull, reflective of the vertebrate baüplan, typically is bilaterally symmetric with right (dextral) and left (sinistral) halves essentially representing mirror images along the midline, both adaptive and abnormal asymmetries have appeared. Herein we provide a basic primer on studies of the asymmetric development of the gnathostome skull, touching briefly on asymmetry as a field of study, then describing the nature of cranial development and finally underscoring evolutionary and functional aspects of left–right asymmetric cephalic development. genesis 52:515–527, 2014. © 2014 Wiley Periodicals, Inc.
The Dogfish <i>Scyliorhinus canicula:</i> A Reference in Jawed Vertebrates
CSH Protocols, Dec 1, 2008
INTRODUCTIONDue to their large size and long generation times, chondrichthyans have been largely ... more INTRODUCTIONDue to their large size and long generation times, chondrichthyans have been largely ignored by geneticists. However, their key phylogenetic position makes them ideal subjects to study the molecular bases of the important morphological and physiological innovations that characterize jawed vertebrates. Such analyses are crucial to understanding the origin of the complex genetic mechanisms unraveled in osteichthyans. The small spotted dogfish Scyliorhinus canicula, a representative of the largest order of extant sharks, presents a number of advantages in this context. Due to its relatively small size among sharks, its abundance, and easy maintenance, the dogfish has been an important model in comparative anatomy and physiology for more than a century. Recently, revived interest has occurred with the development of large-scale transcriptomic and genomic resources, together with the establishment of facilities allowing massive egg and embryo production. These new tools open the way to molecular analyses of the elaborate physiological and sensory systems used by sharks. They also make it possible to take advantage of unique characteristics of these species, such as organ zonation, in analyses of cell proliferation and differentiation. Finally, they offer important perspectives to evolutionary developmental biology that will provide a better understanding of the origin and diversifications of jawed vertebrates. The dogfish whole-genome sequence, which may shortly become accessible, should establish this species as an essential shark reference, complementary to other chondrichthyan models. These analyses are likely to reveal an organism of an underestimated complexity, far from the primitive prototypical gnathostome anticipated in gradistic views.
Pax6 regulates craniofacial form through its control of an essential cephalic ectodermal patterning center
Genesis, Apr 1, 2011
Normal patterning and morphogenesis of the complex skeletal structures of the skull requires an e... more Normal patterning and morphogenesis of the complex skeletal structures of the skull requires an exquisite, reciprocal cross‐talk between the embryonic cephalic epithelia and mesenchyme. The mesenchyme associated with the jaws and the optic and olfactory capsules is derived from a Hox‐negative cranial neural crest (CNC) population that acts much as an equivalence group in its interactions with specific local cephalic epithelial signals. Craniofacial pattern and morphogenesis is therefore controlled in large part through the regulation of these local cephalic epithelial signals. Here, we demonstrate that Pax6 is essential to the formation and maturation of the complex cephalic ectodermal patterning centers that govern the development and morphogenesis of the upper jaws and associated nasal capsules. Previous examinations of the craniofacial skeletal defects associated with Pax6 mutations have suggested that they arise from an optic‐associated blockage in the migration of a specific subpopulation of midbrain CNC to the lateral frontonasal processes. We have addressed an alternative explanation for the craniofacial skeletal defects. We show that in Pax6SeyN/SeyN mutants regional CNC is present by E9.25 while there is already specific disruption in the early ontogenetic elaboration of cephalic ectodermal expression, associated with the nascent lambdoidal junction, of secreted signaling factors (including Fgf8 and Bmp4) and transcription factors (including Six1 and Dlx5) essential for upper jaw and/or nasal capsular development. Pax6 therefore regulates craniofacial form, at stages when CNC has just arrived in the frontonasal region, through its control of surface cephalic ectodermal competence to form an essential craniofacial patterning center. genesis 49:307‐325, 2011. © 2011 Wiley‐Liss, Inc.
Distal spinal muscular atrophy and ataxia with cerebellar atrophy in two unrelated patients; a new phenotypic variant of HRD and recessive KCS syndrome related to TBCE
Neuromuscular Disorders, Oct 1, 2015
International Journal of Molecular Sciences, Apr 28, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Craniofacial development requires an exquisitely timed and positioned cross-talk between the embr... more Craniofacial development requires an exquisitely timed and positioned cross-talk between the embryonic cephalic epithelia and mesenchyme. This cross-talk underlies the precise translation of patterning processes and information into distinct, appropriate skeletal morphologies. The molecular and cellular dialogue includes communication via secreted signaling molecules, including Fgf8, and effectors of their interpretation. Herein, we use genetic attenuation of Fgf8 in mice and perform gain-of-function mousechick chimeric experiments to demonstrate that significant character states of the frontonasal and optic skeletons are dependent on Fgf8. Notably, we show that the normal orientation and polarity of the nasal capsules and their developing primordia are dependent on Fgf8. We further demonstrate that Fgf8 is required for midfacial integration, and provide evidence for a role for Fgf8 in optic capsular development. Taken together, our data highlight Fgf8 signaling in craniofacial development as a plausible target for evolutionary selective pressures.
Brain, May 8, 2021
Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the wh... more Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in five large consanguineous nuclear families allowed us to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report these two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the underlying cause of this novel form of leukodystrophy with ataxia and sensorineural deafness that includes fibrotic cardiomyopathy and hepatopathy as associated features in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as the RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology; mutations in primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.
Suture Neontology and Paleontology: The Bases for Where, When and How Boundaries between Bones Have Been Established and Have Evolved
KARGER eBooks, 2008
Much of what has been written about sutures has either focused on the genetic and biologic etiolo... more Much of what has been written about sutures has either focused on the genetic and biologic etiologies of specific sutural development, maintenance, and pathogenesis or on the utilization of sutures as character states in vertebrate cladistic analyses. There is a much more modest literature explicitly concerned with the evolution of sutures. We provide a small bridge of these literatures by presenting a discussion of the evolutionary biologic bases for the patterns of where, when, and how sutural boundaries between skeletal and dental elements have been established and have evolved. As sutural boundaries do not exist in the absence of the nucleation events that initiate the generation of skeletal elements, we explore historic models seeking to identify the inductive events dictating the specific times and places where a cranial skeletal element forms, the elaboration of its sutural boundaries, and the mechanisms whereby subsequent phyletic changes may be manifested and recognized.
Oncotarget, Jan 7, 2016
During the process of neurogenesis, the stem cell committed to the neuronal cell fate starts a se... more During the process of neurogenesis, the stem cell committed to the neuronal cell fate starts a series of molecular and morphological changes. The understanding of the physio-pathology of mechanisms controlling the molecular and morphological changes occurring during neuronal differentiation is fundamental to the development of effective therapies for many neurologic diseases. Unfortunately, our knowledge of the biological events occurring in the cell during neuronal differentiation is still poor. In this study, we focus preliminarily on the relevance of the cytoskeletal rearrangements, which earlier drive the morphology of the neuronal precursors, and later the migrating/mature neurons. In fact, neuritogenesis, neurite branching, outgrowth and retraction are seminal to the development of a fully functional nervous system. With this in mind, we highlight the importance of iPSC technology to study the processes of cytoskeletal-driven morphological changes during neuronal differentiation.
Developmental Biology, May 1, 2013
Developmental Biology 377 (2013) 428-448 of a lambdoidal junction (formed where the maxillary fir... more Developmental Biology 377 (2013) 428-448 of a lambdoidal junction (formed where the maxillary first arch meets the frontonasal processes) in chondrichthyans, further highlighting the importance of this region for the development and evolution of jaw structure in advanced gnathostomes.
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Papers by Claudia Compagnucci