RESUMO
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.
Assuntos
Córtex Cerebral , Modelos Animais de Doenças , Hiperventilação , Deficiência Intelectual , Neurogênese , Fator de Transcrição 4 , Animais , Fator de Transcrição 4/metabolismo , Fator de Transcrição 4/genética , Feminino , Masculino , Camundongos , Hiperventilação/metabolismo , Hiperventilação/genética , Hiperventilação/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Fácies , Caracteres Sexuais , Interneurônios/metabolismo , Interneurônios/patologia , Células Piramidais/metabolismo , Células Piramidais/patologia , HaploinsuficiênciaRESUMO
Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)
A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)
Assuntos
Humanos , Masculino , Criança , Cromossomos Humanos Par 7/genética , Deficiências do Desenvolvimento/genética , Síndrome de Williams/genética , Duplicação Cromossômica , Transtornos do Desenvolvimento da Linguagem/genética , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/metabolismo , Testes Genéticos , Síndrome de Williams/diagnóstico , Síndrome de Williams/metabolismo , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismoRESUMO
The ZDHHC9 gene encodes the Zinc Finger DHHC-Type Containing 9 protein that functions as a palmitoyltransferase. Variants in this gene have been reported as the cause of Raymond-type X-linked intellectual disability with only 16 families described in the literature. This study reviews molecular and clinical data from previously reported patients and reports the case of a 13-year-old patient with a splicing variant in ZDHHC9 presenting intellectual disability, developmental delay, facial dysmorphisms, and skeletal defects. Although intellectual disability and developmental delay with severe speech delay have been reported in all cases with available clinical data, the remaining clinical signs differ significantly between patients. Missense, nonsense, frameshift, and splicing variants, in addition to large exonic deletions, have been described suggesting a loss of function mechanism. Though variants are distributed in almost all exons, most missense and nonsense variants affect arginine residues located in the cytoplasmic domains of this transmembrane protein, suggesting possible mutational hotspots.
Assuntos
Deficiência Intelectual , Adolescente , Humanos , Éxons/genética , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação , FenótipoRESUMO
NEXMIF pathogenic variants have been known to produce a wide spectrum of X-linked intellectual disability (ID) in both males and females. Thus far, few individuals from diverse populations have been described with NEXMIF-related disorders. Herein, we report three individuals with NEXMIF pathogenic variants, the first two are the only males of Korean and Vietnamese descent described with this disorder to our knowledge. The last patient is a Hispanic female who harbors the same pathogenic variant as a previously described Caucasian individual, but with differing clinical presentation. These patients present with many classic symptoms of NEXMIF-related disorders including ID, epilepsy, developmental delay, and dysmorphic features. In addition, they have symptoms that have not been thoroughly described in the literature, including allergies with multiple anaphylactic events and hypothyroidism. This report is intended to raise awareness and educate about the clinical signs that may prompt testing for NEXMIF-related disorders.
Assuntos
Deficiência Intelectual , Proteínas do Tecido Nervoso , Povo Asiático/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , República da CoreiaRESUMO
Alopecia, neurologic defects, and endocrinopathy (ANE) syndrome is a rare ribosomopathy known to be caused by a p.(Leu351Pro) variant in the essential, conserved, nucleolar large ribosomal subunit (60S) assembly factor RBM28. We report the second family of ANE syndrome to date and a female pediatric ANE syndrome patient. The patient presented with alopecia, craniofacial malformations, hypoplastic pituitary, and hair and skin abnormalities. Unlike the previously reported patients with the p.(Leu351Pro) RBM28 variant, this ANE syndrome patient possesses biallelic precursor messenger RNA (pre-mRNA) splicing variants at the 5' splice sites of exon 5 (ΔE5) and exon 8 (ΔE8) of RBM28 (NM_018077.2:c.[541+1_541+2delinsA]; [946G > T]). In silico analyses and minigene splicing experiments in cells indicate that each splice variant specifically causes skipping of its respective mutant exon. Because the ΔE5 variant results in an in-frame 31 amino acid deletion (p.(Asp150_Lys180del)) in RBM28 while the ΔE8 variant leads to a premature stop codon in exon 9, we predicted that the ΔE5 variant would produce partially functional RBM28 but the ΔE8 variant would not produce functional protein. Using a yeast model, we demonstrate that the ΔE5 variant does indeed lead to reduced overall growth and large subunit ribosomal RNA (rRNA) production and pre-rRNA processing. In contrast, the ΔE8 variant is comparably null, implying that the partially functional ΔE5 RBM28 protein enables survival but precludes correct development. This discovery further defines the underlying molecular pathology of ANE syndrome to include genetic variants that cause aberrant splicing in RBM28 pre-mRNA and highlights the centrality of nucleolar processes in human genetic disease.
Assuntos
Alopecia/metabolismo , Nucléolo Celular/metabolismo , Doenças do Sistema Endócrino/metabolismo , Deficiência Intelectual/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Subunidades Ribossômicas Maiores/metabolismo , Adulto , Alopecia/genética , Brasil , Doenças do Sistema Endócrino/genética , Éxons , Feminino , Células HEK293 , Cabelo/metabolismo , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Linhagem , Precursores de RNA/metabolismo , Processamento Pós-Transcricional do RNA , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Subunidades Ribossômicas Maiores/genética , Saccharomyces cerevisiae , Adulto JovemRESUMO
Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.
Assuntos
Transtorno Autístico/genética , Fator de Iniciação 3 em Eucariotos/genética , Deleção de Genes , Deficiência Intelectual/genética , Complexos Multiproteicos/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Serina-Treonina Quinases TOR/genética , Adolescente , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Estudos de Casos e Controles , Fator de Iniciação 3 em Eucariotos/metabolismo , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Deficiência Intelectual/metabolismo , Deficiência Intelectual/fisiopatologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Iniciação Traducional da Cadeia Peptídica , Cultura Primária de Células , Ligação Proteica , Fatores de Troca de Nucleotídeo Guanina Rho/deficiência , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , TransfecçãoRESUMO
Synaptic function is crucially dependent on the spatial organization of the presynaptic and postsynaptic apparatuses and the juxtaposition of both membrane compartments. This precise arrangement is achieved by a protein network at the submembrane region of each cell that is built around scaffold proteins. The membrane-associated guanylate kinase (MAGUK) family of proteins is a widely expressed and well-conserved group of proteins that plays an essential role in the formation and regulation of this scaffolding. Here, we review general features of this protein family, focusing on the discs large and calcium/calmodulin-dependent serine protein kinase subfamilies of MAGUKs in the formation, function, and plasticity of synapses.
Assuntos
Guanilato Quinases/metabolismo , Neurônios/citologia , Sinapses/metabolismo , Animais , Regulação da Expressão Gênica/fisiologia , Guanilato Quinases/classificação , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Aprendizagem/fisiologia , Proteínas de Membrana/metabolismo , Estrutura Terciária de Proteína/fisiologiaRESUMO
Systematic detection of inborn errors of metabolism (IEM) has usually encountered difficulties in developing countries. We present our experience in a high-risk population in Mexico between 1973 and 1998 with particular reference to the last 10 years, during which time infrastructure and support were considerably improved. Only disorders of intermediary metabolism were sought. The total number of patients studied is not available, but in the last 10 years, patients numbered 5,186. Routine metabolic screening was performed on all patients, with additional tests according to the clinical picture and screening results. The referral criteria have increasingly diversified, one-third being neurological conditions. Of the referrals, 33.8% were from pediatricians (31.1% of whom were at critical medicine departments) and the remainder from specialists. The number of diagnosed patients has increased to 1 per 43.9 patients studied. Amino acid defects have been the most prevalent, the proportion of organic acid and carbohydrate disorders having increased in the last 10 years, associated with improved diagnostic facilities. The most frequently diagnosed diseases were PKU, type 1a glycogen storage, and maple syrup urine disease (MSUD), their frequency apparently varying among different regions of Mexico. Other results of our program include training of specialists and technicians, development of the Latin American Metabolic Information Network, a procedure to locally prepare a special food product low in phenylalanine for the treatment of PKU patients, and extension of approaches for these disorders to the investigation metabolic derangements of infant malnutrition. This work demonstrates that inherited metabolic diseases constitute a significant load in pediatric pathology and that their study can and should be pursued in developing nations.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Pessoal Técnico de Saúde/educação , Criança , Pré-Escolar , Países em Desenvolvimento , Educação Médica , Feminino , Testes Genéticos , Genética Médica/educação , Genética Médica/métodos , Genética Médica/organização & administração , Acessibilidade aos Serviços de Saúde , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , México/epidemiologia , Hipotonia Muscular/epidemiologia , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Triagem Neonatal , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Recursos HumanosRESUMO
Introducción. La finalidad del examen de tamiz neonatal es la detección precoz de las alteraciones congénitas del metabolismo que ocasionan retraso mental; de ellas la más común es el hipotiroidismo congénito (HTC). El objetivo de estudio fue conocer la incidencia del HTC detectado por tamiz neonatal en el Instituto Nacional de Perinatología. Material y métodos. Se revisaron los casos corroborados de HTC en el período de 1990 a 1993, que fueron identificados a través del programa de tamiz neonatal del Instituto. Resultados. En el período de estudio se tamizaron 13,510 recién nacidos (RN), se detectaron 10 casos de HTC, lo que proporcionó una incidencia de 1 caso por cada 1,428 niños tamizados. Se tamizó en promedio el 74.4 por ciento del total de RN vivos. Conclusiones. La incidencia de HTC fue superior a otros estudios realizados en México. Es necesario incrementar la capacitación de RN en el programa de tamiz neonatal