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1.
Neurobiol Dis ; 198: 106558, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38852754

RESUMEN

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flnaflox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.


Asunto(s)
Corteza Cerebral , Filaminas , Proteína de Unión al GTP rac1 , Animales , Ratones , Factores Despolimerizantes de la Actina/metabolismo , Corteza Cerebral/metabolismo , Filaminas/metabolismo , Filaminas/genética , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Ratones Transgénicos , Neurogénesis/fisiología , Neuronas/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/genética , Heterotopia Nodular Periventricular/genética , Heterotopia Nodular Periventricular/metabolismo , Heterotopia Nodular Periventricular/patología , Células Piramidales/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rac1/genética
2.
Neurobiol Dis ; 173: 105856, 2022 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-36070836

RESUMEN

Synaptopathies are a class of neurodevelopmental disorders caused by modification in genes coding for synaptic proteins. These proteins oversee the process of neurotransmission, mainly controlling the fusion and recycling of synaptic vesicles at the presynaptic terminal, the expression and localization of receptors at the postsynapse and the coupling between the pre- and the postsynaptic compartments. Murine models, with homozygous or heterozygous deletion for several synaptic genes or knock-in for specific pathogenic mutations, have been developed. They have proved to be extremely informative for understanding synaptic physiology, as well as for clarifying the patho-mechanisms leading to developmental delay, epilepsy and motor, cognitive and social impairments that are the most common clinical manifestations of neurodevelopmental disorders. However, the onset of these disorders emerges during infancy and adolescence while the behavioral phenotyping is often conducted in adult mice, missing important information about the impact of synaptic development and maturation on the manifestation of the behavioral phenotype. Here, we review the main achievements obtained by behavioral testing in murine models of synaptopathies and propose a battery of behavioral tests to improve classification, diagnosis and efficacy of potential therapeutic treatments. Our aim is to underlie the importance of studying behavioral development and better focusing on disease onset and phenotypes.


Asunto(s)
Trastornos del Neurodesarrollo , Sinapsis , Animales , Ratones , Trastornos del Neurodesarrollo/metabolismo , Terminales Presinápticos , Sinapsis/metabolismo , Transmisión Sináptica/genética , Vesículas Sinápticas
3.
Brain ; 142(12): 3876-3891, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31688942

RESUMEN

Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/genética , Encéfalo/fisiopatología , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Progresión de la Enfermedad , Electroencefalografía , Femenino , Humanos , Lactante , Lisosomas/fisiología , Imagen por Resonancia Magnética , Masculino , Mutación , Linaje , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/fisiopatología , Secuenciación del Exoma
4.
Proc Natl Acad Sci U S A ; 111(6): 2337-42, 2014 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-24469796

RESUMEN

Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.


Asunto(s)
Factores de Ribosilacion-ADP/fisiología , Proteínas Portadoras/fisiología , Movimiento Celular/fisiología , Neuronas/citología , Factor 6 de Ribosilación del ADP , Animales , Encéfalo/fisiología , Proteínas Portadoras/genética , Células Cultivadas , Dendritas/fisiología , Proteínas Activadoras de GTPasa , Técnicas de Silenciamiento del Gen , Ácido Glutámico/metabolismo , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Ratas , Sinapsis/metabolismo
5.
Ann Neurol ; 76(2): 206-12, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24782409

RESUMEN

OBJECTIVE: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. METHODS: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. RESULTS: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. INTERPRETATION: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.


Asunto(s)
Ceramidas/biosíntesis , Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/metabolismo , Epilepsias Mioclónicas Progresivas/metabolismo , Esfingosina N-Aciltransferasa/metabolismo , Argelia , Demencia/genética , Demencia/metabolismo , Retículo Endoplásmico/genética , Humanos , Proteínas de la Membrana/genética , Mutación/genética , Epilepsias Mioclónicas Progresivas/genética , Hermanos , Esfingosina N-Aciltransferasa/genética
6.
Acta Physiol (Oxf) ; : e14186, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38837572

RESUMEN

AIM: Understanding the physiological role of ATP6V1A, a component of the cytosolic V1 domain of the proton pump vacuolar ATPase, in regulating neuronal development and function. METHODS: Modeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy. RESULTS: Atp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V1 subunits, that leads to impairment of lysosomal pH-regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons. CONCLUSIONS: These data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties.

7.
Eur J Hum Genet ; 32(3): 342-349, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38177406

RESUMEN

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.


Asunto(s)
Enfermedades Musculares , Distrofias Musculares , Humanos , Distroglicanos/genética , Distroglicanos/metabolismo , Haploinsuficiencia , Distrofias Musculares/genética , Músculo Esquelético/patología , Enfermedades Musculares/patología
8.
Hum Mutat ; 34(6): 869-72, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23526554

RESUMEN

Early-onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug-resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug-resistant early-onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction.


Asunto(s)
Proteínas Portadoras/genética , Heterocigoto , Mutación , Espasmos Infantiles/genética , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Exoma , Femenino , Proteínas Activadoras de GTPasa , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Fenotipo , Espasmos Infantiles/diagnóstico
9.
Am J Hum Genet ; 87(3): 365-70, 2010 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-20727515

RESUMEN

Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal-recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders.


Asunto(s)
Factores de Ribosilacion-ADP/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Epilepsias Mioclónicas/genética , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Mutación/genética , Factor 6 de Ribosilación del ADP , Animales , Secuencia de Bases , Análisis Mutacional de ADN , Familia , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana , Ratones , Datos de Secuencia Molecular , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas del Tejido Nervioso , Linaje , Unión Proteica
10.
Front Pediatr ; 11: 1326552, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38178912

RESUMEN

Rotatin, encoded by the RTTN gene, is a centrosomal protein with multiple, emerging functions, including left-right specification, ciliogenesis, and neuronal migration. Recessive variants in RTTN are associated with a neurodevelopmental disorder with microcephaly and malformations of cortical development known as "Microcephaly, short stature, and polymicrogyria with seizures" (MSSP, MIM #614833). Affected individuals show a wide spectrum of clinical manifestations like intellectual disability, poor/absent speech, short stature, microcephaly, and congenital malformations. Here, we report a subject showing a distinctive neuroradiological phenotype and harboring novel biallelic variants in RTTN: the c.5500A>G, p.(Asn1834Asp), (dbSNP: rs200169343, ClinVar ID:1438510) and c.19A>G, p.(Ile7Val), (dbSNP: rs201165599, ClinVar ID:1905275) variants. In particular brain magnetic resonance imaging (MRI) showed a peculiar pattern, with cerebellar hypo-dysplasia, and multiple arachnoid cysts in the lateral cerebello-medullary cisterns, in addition to left Meckel cave. Thus, we compare his phenotypic features with current literature, speculating a possible role of newly identified RTTN variants in his clinical picture, and supporting a relevant variability in this emerging condition.

11.
Front Cell Neurosci ; 14: 39, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32231521

RESUMEN

Autophagy is a highly conserved degradative process that conveys dysfunctional proteins, lipids, and organelles to lysosomes for degradation. The post-mitotic nature, complex and highly polarized morphology, and high degree of specialization of neurons make an efficient autophagy essential for their homeostasis and survival. Dysfunctional autophagy occurs in aging and neurodegenerative diseases, and autophagy at synaptic sites seems to play a crucial role in neurodegeneration. Moreover, a role of autophagy is emerging for neural development, synaptogenesis, and the establishment of a correct connectivity. Thus, it is not surprising that defective autophagy has been demonstrated in a spectrum of neurodevelopmental disorders, often associated with early-onset epilepsy. Here, we discuss the multiple roles of autophagy in neurons and the recent experimental evidence linking neurodevelopmental disorders with epilepsy to genes coding for autophagic/lysosomal system-related proteins and envisage possible pathophysiological mechanisms ranging from synaptic dysfunction to neuronal death.

12.
Cell Death Differ ; 26(11): 2464-2478, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30858606

RESUMEN

Mutations in TBC1D24 are described in patients with a spectrum of neurological diseases, including mild and severe epilepsies and complex syndromic phenotypes such as Deafness, Onycodystrophy, Osteodystrophy, Mental Retardation and Seizure (DOORS) syndrome. The product of TBC1D24 is a multifunctional protein involved in neuronal development, regulation of synaptic vesicle trafficking, and protection from oxidative stress. Although pathogenic mutations in TBC1D24 span the entire coding sequence, no clear genotype/phenotype correlations have emerged. However most patients bearing predicted loss of function mutations exhibit a severe neurodevelopmental disorder. Aim of the study is to investigate the impact of TBC1D24 knockdown during the first stages of neuronal differentiation when axonal specification and outgrowth take place. In rat cortical primary neurons silenced for TBC1D24, we found defects in axonal specification, the maturation of axonal initial segment and action potential firing. The axonal phenotype was accompanied by an impairment of endocytosis at the growth cone and an altered activation of the TBC1D24 molecular partner ADP ribosylation factor 6. Accordingly, acute knockdown of TBC1D24 in cerebrocortical neurons in vivo analogously impairs callosal projections. The axonal defect was also investigated in human induced pluripotent stem cell-derived neurons from patients carrying TBC1D24 mutations. Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy. Our data reveal that alterations of membrane trafficking at the growth cone induced by TBC1D24 loss of function cause axonal and excitability defects. The axonal phenotype correlates with the disease severity and highlight an important role for TBC1D24 in connectivity during brain development.


Asunto(s)
Transporte Axonal/fisiología , Axones/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Proyección Neuronal/fisiología , Neuronas/metabolismo , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/metabolismo , Animales , Proteínas Activadoras de GTPasa/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Enfermedades del Sistema Nervioso/genética , Neurogénesis/fisiología , Estrés Oxidativo/fisiología , Dominios Proteicos/genética , Ratas , Ratas Wistar
13.
Dialogues Clin Neurosci ; 20(4): 255-266, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30936766

RESUMEN

The development of the cerebral cortex requires complex sequential processes that have to be precisely orchestrated. The localization and timing of neuronal progenitor proliferation and of neuronal migration define the identity, laminar positioning, and specific connectivity of each single cortical neuron. Alterations at any step of this organized series of events-due to genetic mutations or environmental factors-lead to defined brain pathologies collectively known as malformations of cortical development (MCDs), which are now recognized as a leading cause of drug-resistant epilepsy and intellectual disability. In this heterogeneous group of disorders, macroscopic alterations of brain structure (eg, heterotopic nodules, small or absent gyri, double cortex) can be recognized and probably subtend a general reorganization of neuronal circuits. In this review, we provide an overview of the molecular mechanisms that are implicated in the generation of genetic MCDs associated with aberrations at various steps of neurogenesis and cortical development.


El desarrollo de la corteza cerebral requiere de una secuencia de complejos procesos que tienen que estar coordinados con precisión. La localización y la cronología de la proliferación de las neuronas precursoras y de la migración neuronal definen la identidad, el posicionamiento laminar y la conectividad específica de cada una de las neuronas corticales. Las alteraciones en cualquier etapa de esta serie organizada de acontecimientos- debidas a mutaciones genéticas o a factores ambientales- llevan a patologías cerebrales definidas que en conjunto se denominan malformaciones del desarrollo cortical (MDC), las cuales son reconocidas actualmente como causa de epilepsia resistente a fármacos e incapacidad intelectual. En este grupo heterogéneo de trastornos, las alteraciones macroscópicas de la estructura cerebral (por ej. nódulos heterotópicos, giros pequeños o ausentes, doble corteza) pueden ser reconocidas y es probable que subtiendan a una reorganización general de los circuitos neuronales. En esta revisión se entrega una panorámica de los mecanismos moleculares que se han involucrado en la generación de las MDC asociadas con aberraciones en varias etapas de la neurogénesis y del desarrollo cortical.


Le développement du cortex cérébral fait appel à des processus séquentiels complexes qui doivent être orchestrés précisément. La localisation et la chronologie de la prolifération de neurones précurseurs et celles de la migration neuronale définissent l'identité, le positionnement laminaire et la connectivité spécifique de chaque neurone cortical unique. Toute modification, quel que soit le stade de ces séries organisées d'événements (en raison de mutations génétiques ou de facteurs environnementaux), entraîne des pathologies cérébrales définies, globalement connues sous le terme de malformations du développement cortical (MDC). Ces malformations sont maintenant reconnues comme principalement responsables de la résistance aux médicaments contre l'épilepsie et du déficit intellectuel. Dans ce groupe hétérogène de maladies, les modifications macroscopiques de la structure cérébrale (par exemple, nodules hétérotopiques, gyrus petit ou absent, double cortex) peuvent être identifiées et probablement sous-tendre une réorganisation générale des circuits neuronaux. Cet article présente une vue d'ensemble des mécanismes moléculaires impliqués dans l'apparition de MDC génétiques associées à des aberrations à des stades différents de la neurogenèse et du développement cortical.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Neurogénesis/fisiología , Neuronas/citología , Animales , Humanos , Red Nerviosa/crecimiento & desarrollo
14.
Biochem Biophys Res Commun ; 363(4): 1033-7, 2007 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17923109

RESUMEN

Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophies. Mutations in POMT2 gene have been identified in patients with congenital muscular dystrophy and brain involvement, either characterized by a Walker-Warburg/muscle-eye-brain phenotype, or by microcephaly, mental retardation, and cerebellar hypoplasia. We identified a POMT2 homozygous missense mutation in a girl with a mild limb-girdle muscular dystrophy (LGMD) phenotype, marked elevated serum creatine kinase levels, and absence of brain involvement. Muscle biopsy revealed myopathic and inflammatory changes and severe alpha-dystroglycan reduction. In view of the remarkable mild clinical picture, we propose to designate this phenotype as LGMD2N.


Asunto(s)
Manosiltransferasas/genética , Manosiltransferasas/metabolismo , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Secuencia de Bases , Biopsia , Preescolar , Femenino , Humanos , Inflamación/complicaciones , Inflamación/genética , Inflamación/metabolismo , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/genética , Mutación/genética
15.
Neuromuscul Disord ; 17(1): 23-7, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17140792

RESUMEN

Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K(+) channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.


Asunto(s)
Salud de la Familia , Síndrome de Isaacs/genética , Síndrome de Isaacs/fisiopatología , Mutación , Canales de Potasio/genética , Adulto , Anciano , Niño , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Masculino , Linaje
16.
J Vis Exp ; (130)2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29286390

RESUMEN

Birth defects that involve the cerebral cortex - also known as malformations of cortical development (MCD) - are important causes of intellectual disability and account for 20-40% of drug-resistant epilepsy in childhood. High-resolution brain imaging has facilitated in vivo identification of a large group of MCD phenotypes. Despite the advances in brain imaging, genomic analysis and generation of animal models, a straightforward workflow to systematically prioritize candidate genes and to test functional effects of putative mutations is missing. To overcome this problem, an experimental strategy enabling the identification of novel causative genes for MCD was developed and validated. This strategy is based on identifying candidate genomic regions or genes via array-CGH or whole-exome sequencing and characterizing the effects of their inactivation or of overexpression of specific mutations in developing rodent brains via in utero electroporation. This approach led to the identification of the C6orf70 gene, encoding for a putative vesicular protein, to the pathogenesis of periventricular nodular heterotopia, a MCD caused by defective neuronal migration.


Asunto(s)
Encéfalo/patología , Hibridación Genómica Comparativa/métodos , Electroporación/métodos , Secuenciación del Exoma/métodos , Malformaciones del Desarrollo Cortical/genética , Animales , Química Encefálica , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Modelos Animales de Enfermedad , Femenino , Humanos , Malformaciones del Desarrollo Cortical/sangre , Malformaciones del Desarrollo Cortical/patología , Embarazo , Ratas
17.
Arch Neurol ; 63(10): 1491-5, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17030669

RESUMEN

BACKGROUND: Muscle-eye-brain disease is a congenital muscular dystrophy with eye and brain involvement due to POMGnT1 mutations. OBJECTIVE: To describe the clinical and molecular features of 3 Italian patients with POMGnT1 mutations. DESIGN: Case reports. PATIENTS: One patient had muscle and brain abnormalities without eye involvement. Two patients had a classic muscle-eye-brain disease phenotype with different levels of clinical severity. RESULTS: Brain magnetic resonance imaging showed cortical malformation and posterior fossa involvement. Immunofluorescence for glycosylated alpha-dystroglycan performed on muscle biopsy specimens demonstrated an absent signal in 1 patient and reduced staining in 2 patients. Molecular analysis identified 5 mutations, 2 of which are novel. CONCLUSION: This article adds to what is known about the genotype-phenotype correlation and expands our awareness of the clinical spectrum associated with POMGnT1 mutations.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Distrofias Musculares/congénito , Distrofias Musculares/genética , Mutación/genética , N-Acetilglucosaminiltransferasas/genética , Adulto , Encéfalo/anomalías , Encéfalo/metabolismo , Encéfalo/fisiopatología , Niño , Secuencia Conservada/genética , Análisis Mutacional de ADN , Distroglicanos/metabolismo , Femenino , Genotipo , Productos Finales de Glicación Avanzada/genética , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofias Musculares/fisiopatología , Fenotipo , Retina/metabolismo , Retina/fisiopatología , Homología de Secuencia de Ácido Nucleico , Síndrome
18.
Elife ; 52016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26731518

RESUMEN

Recycling of synaptic vesicles (SVs) is a fundamental step in the process of neurotransmission. Endocytosed SV can travel directly into the recycling pool or recycle through endosomes but little is known about the molecular actors regulating the switch between these SV recycling routes. ADP ribosylation factor 6 (Arf6) is a small GTPase known to participate in constitutive trafficking between plasma membrane and early endosomes. Here, we have morphologically and functionally investigated Arf6-silenced hippocampal synapses and found an activity dependent accumulation of synaptic endosome-like organelles and increased release-competent docked SVs. These features were phenocopied by pharmacological blockage of Arf6 activation. The data reveal an unexpected role for this small GTPase in reducing the size of the readily releasable pool of SVs and in channeling retrieved SVs toward direct recycling rather than endosomal sorting. We propose that Arf6 acts at the presynapse to define the fate of an endocytosed SV.


Asunto(s)
Factores de Ribosilacion-ADP/metabolismo , Hipocampo/fisiología , Sinapsis/fisiología , Vesículas Sinápticas/metabolismo , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/antagonistas & inhibidores , Factores de Ribosilacion-ADP/genética , Animales , Silenciador del Gen , Ratas Sprague-Dawley
19.
Eur J Hum Genet ; 24(6): 838-43, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26395558

RESUMEN

Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5A could be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novo translocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5A gene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5A in 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5A microdeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5A with susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.


Asunto(s)
Trastorno del Espectro Autista/genética , Deleción Cromosómica , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/diagnóstico , Niño , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 5/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Masculino , Herencia Paterna , Semaforinas , Translocación Genética
20.
Neurology ; 87(1): 77-85, 2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27281533

RESUMEN

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.


Asunto(s)
Proteínas Portadoras/genética , Epilepsia/genética , Epilepsia/fisiopatología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Proteínas Portadoras/metabolismo , Aumento de la Célula , Células Cultivadas , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/psicología , Femenino , Proteínas Activadoras de GTPasa , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Proteínas de la Membrana , Ratones , Mutación , Proteínas del Tejido Nervioso , Neuritas/fisiología , Examen Físico , Adulto Joven
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