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1.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

3.
Hum Mutat ; 39(1): 23-39, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29068161

RESUMO

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Genes DCC , Estudos de Associação Genética , Mutação , Fenótipo , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Bases de Dados Genéticas , Humanos , Imagem por Ressonância Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , Síndrome
4.
Neural Dev ; 12(1): 9, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28558801

RESUMO

The corpus callosum forms the major interhemispheric connection in the human brain and is unique to eutherian (or placental) mammals. The developmental events associated with the evolutionary emergence of this structure, however, remain poorly understood. A key step in callosal formation is the prior remodeling of the interhemispheric fissure by embryonic astroglial cells, which then subsequently act as a permissive substrate for callosal axons, enabling them to cross the interhemispheric midline. However, whether astroglial-mediated interhemispheric remodeling is unique to eutherian mammals, and thus possibly associated with the phylogenetic origin of the corpus callosum, or instead is a general feature of mammalian brain development, is not yet known. To investigate this, we performed a comparative analysis of interhemispheric remodeling in eutherian and non-eutherian mammals, whose lineages branched off before the evolution of the corpus callosum. Whole brain MRI analyses revealed that the interhemispheric fissure is retained into adulthood in marsupials and monotremes, in contrast to eutherians (mice), in which the fissure is significantly remodeled throughout development. Histological analyses further demonstrated that, while midline astroglia are present in developing marsupials, these cells do not intercalate with one another through the intervening interhemispheric fissure, as they do in developing mice. Thus, developing marsupials do not undergo astroglial-mediated interhemispheric remodeling. As remodeling of the interhemispheric fissure is essential for the subsequent formation of the corpus callosum in eutherians, our data highlight the role of astroglial-mediated interhemispheric remodeling in the evolutionary origin of the corpus callosum.


Assuntos
Astrócitos/fisiologia , Corpo Caloso/crescimento & desenvolvimento , Eutérios/crescimento & desenvolvimento , Telencéfalo/crescimento & desenvolvimento , Animais , Evolução Biológica , Corpo Caloso/anatomia & histologia , Eutérios/anatomia & histologia , Especificidade da Espécie
5.
Nat Genet ; 49(4): 511-514, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28250454

RESUMO

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.


Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Mutação/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Encéfalo/patologia , Corpo Caloso/patologia , Receptor DCC , Família , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/patologia , Penetrância , Fenótipo
7.
Neuroimage ; 139: 259-270, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27338515

RESUMO

Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the experience by social isolation impairs white matter microstructures in the prefrontal cortex. However, the effect of social isolation may involve highly distributed brain networks, and therefore cannot be fully explained by a change of a single region. Here, we compared the connectomes of adolescent socially-isolated mice and normal-housed controls via diffusion magnetic resonance imaging. The isolated mice displayed an abnormal connectome, characterized by an increase in degree and reductions in measures such as modularity, small-worldness, and betweenness. The increase in degree was most evident in the dorsolateral orbitofrontal cortex, entorhinal cortex, and perirhinal cortex. In a connection-wise comparison, we revealed that most of the abnormal edges were inter-modular and inter-hemispheric connections of the dorsolateral orbitofrontal cortex. Further tractography-based analyses and histological examinations revealed microstructural changes in the forceps minor and lateral-cortical tracts that were associated with the dorsolateral orbitofrontal cortex. These changes of connectomes were correlated with fear memory deficits and hyper-locomotion activities induced by social isolation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may primarily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome.


Assuntos
Encéfalo/patologia , Conectoma , Isolamento Social , Animais , Condicionamento Clássico , Imagem de Difusão por Ressonância Magnética , Medo , Feminino , Masculino , Memória de Curto Prazo , Camundongos Endogâmicos C57BL , Atividade Motora , Vias Neurais/patologia
8.
Development ; 142(21): 3746-57, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26534986

RESUMO

Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.


Assuntos
Giro do Cíngulo/metabolismo , Proteínas de Homeodomínio/metabolismo , Neuropilina-1/metabolismo , Fatores de Transcrição/metabolismo , Agenesia do Corpo Caloso/embriologia , Agenesia do Corpo Caloso/genética , Animais , Axônios/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Semaforinas/metabolismo
9.
Brain ; 137(Pt 6): 1579-613, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24477430

RESUMO

The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.


Assuntos
Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Predisposição Genética para Doença/genética , Agenesia do Corpo Caloso/fisiopatologia , Animais , Corpo Caloso/patologia , Modelos Animais de Doenças , Humanos , Mutação/genética
10.
Int J Radiat Oncol Biol Phys ; 87(1): 148-52, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23920394

RESUMO

PURPOSE: To evaluate the correlations and relative contributions of components of a radiation oncology-specific patient satisfaction survey to their overall satisfaction scores. METHODS AND MATERIALS: From September 2006 through August 2012, we prospectively collected data from 8069 patients receiving radiation treatments with a 26-question survey. Each question was rated on a 10-point Likert scale. We analyzed the correlation between scores for each question and the overall satisfaction question. We also dichotomized the scores to reflect satisfaction versus dissatisfaction and used logistic regression to assess the relationship between items in 4 domains (the patient-provider relationship, access and environmental issues, wait times, and educational information) and overall satisfaction. RESULTS: Scores on all questions correlated with overall patient satisfaction scores (P<.0001). Satisfaction with patient-provider relationships had the greatest influence on overall satisfaction (R(2)=0.4219), followed by wait times (R(2)=0.4000), access/environment (R(2)=0.3837), and patient education (R(2)=0.3700). The specific variables with the greatest effect on patient satisfaction were the care provided by radiation therapists (odds ratio 1.91) and pain management (odds ratio 1.29). CONCLUSIONS: We found that patients' judgment of provider relationships in an outpatient radiation oncology setting were the greatest contributors to their overall satisfaction ratings. Other measures typically associated with patient satisfaction (phone access, scheduling, and ease of the check-in process) correlated less strongly with overall satisfaction. These findings may be useful for other practices preparing to assess patient ratings of quality of care.


Assuntos
Neoplasias/radioterapia , Satisfação do Paciente , Relações Profissional-Paciente , Assistência ao Convalescente , Coleta de Dados , Humanos , Neoplasias/psicologia , Cuidados de Enfermagem , Manejo da Dor , Equipe de Assistência ao Paciente , Radioterapia (Especialidade)
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