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1.
Clin Genet ; 96(3): 254-260, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31170314

RESUMO

Myoclonic-atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array-CGH and whole-exome sequencing in 27 patients. We considered non-synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease-causing variants in 11 patients (41%). Single variants were found in some known epilepsy-associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.

2.
J Clin Invest ; 129(3): 1240-1256, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620337

RESUMO

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

3.
Elife ; 72018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311906

RESUMO

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.

4.
Cell ; 175(2): 488-501.e22, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30270045

RESUMO

Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cyclic GMP-AMP synthase (cGAS) is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

5.
Am J Med Genet A ; 176(9): 1981-1984, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30178921

RESUMO

The clinical presentation of distal duplications of the long arm of chromosome (chr) 16 is currently not well described. Only one case of microduplication of chr16q22.1 and another involving the chr16q22.1q23.1 region have been reported so far. Here, using array comparative genomic hybridization, we identified a second case of chr16q22.1q23.1 duplication in a Vietnamese boy, who shares significant clinical phenotype with the previously described case. Aside from developmental delay, intellectual disability and midface hypoplasia, our patient also displays a forked tongue, visual impairment and external ptosis. Our report further expands the clinical spectrum associated with duplication of this region.

6.
Mol Autism ; 9: 38, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951184

RESUMO

Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs have emerged as important modulators of brain development and neuronal function and are implicated in several neurological diseases. Previous studies found miR-146a upregulation is the most common miRNA deregulation event in neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability (ID). Yet, how miR-146a upregulation affects the developing fetal brain remains unclear. Methods: We analyzed the expression of miR-146a in the temporal lobe of ASD children using Taqman assay. To assess the role of miR-146a in early brain development, we generated and characterized stably induced H9 human neural stem cell (H9 hNSC) overexpressing miR-146a using various cell and molecular biology techniques. Results: We first showed that miR-146a upregulation occurs early during childhood in the ASD brain. In H9 hNSC, miR-146a overexpression enhances neurite outgrowth and branching and favors differentiation into neuronal like cells. Expression analyses revealed that 10% of the transcriptome was deregulated and organized into two modules critical for cell cycle control and neuronal differentiation. Twenty known or predicted targets of miR-146a were significantly deregulated in the modules, acting as potential drivers. The two modules also display distinct transcription profiles during human brain development, affecting regions relevant for ASD including the neocortex, amygdala, and hippocampus. Cell type analyses indicate markers for pyramidal, and interneurons are highly enriched in the deregulated gene list. Up to 40% of known markers of newly defined neuronal lineages were deregulated, suggesting that miR-146a could participate also in the acquisition of neuronal identities. Conclusion: Our results demonstrate the dynamic roles of miR-146a in early neuronal development and provide new insight into the molecular events that link miR-146a overexpression to impaired neurodevelopment. This, in turn, may yield new therapeutic targets and strategies.


Assuntos
Transtorno do Espectro Autista/genética , MicroRNAs/genética , Células-Tronco Neurais/metabolismo , Neurogênese , Transtorno do Espectro Autista/metabolismo , Linhagem Celular , Linhagem da Célula , Criança , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Células-Tronco Neurais/citologia , Lobo Temporal/citologia , Lobo Temporal/metabolismo , Regulação para Cima
7.
Brain ; 141(7): 1998-2013, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29878067

RESUMO

Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

8.
Am J Med Genet A ; 176(5): 1091-1098, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29681083

RESUMO

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.

9.
Eur J Hum Genet ; 26(6): 912-918, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29483668

RESUMO

Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes.

10.
Nat Commun ; 8: 15910, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28675162

RESUMO

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.

11.
Neurosci Biobehav Rev ; 71: 729-738, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27793596

RESUMO

Autism spectrum disorders (ASD) are heritable neurodevelopmental conditions characterized by impairment in social interaction and communication and restricted, repetitive, stereotyped patterns of behavior. ASD likely involve deregulation of multiple genes related to brain function and development. MicroRNAs (miRNAs) are post-transcriptional regulators that play key roles in brain development, synapse formation and fine-tuning of genes underlying synaptic plasticity and memory formation. Here, we review recent studies providing genetic and molecular links between miRNA deregulation and ASD pathophysiology. These findings highlight the potential of miRNAs as both biomarkers and therapeutic tools in ASD.


Assuntos
Transtorno do Espectro Autista , Biomarcadores , Humanos , MicroRNAs , Plasticidade Neuronal
13.
Orphanet J Rare Dis ; 11(1): 57, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27146152

RESUMO

BACKGROUND: Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don't suggest a specific molecular diagnosis. METHODS: To genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models. RESULTS: We successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject. CONCLUSIONS: This study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency.


Assuntos
Atrofia/diagnóstico , Atrofia/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma/genética , Mutação/genética , Análise de Sequência de DNA/métodos , Encéfalo/metabolismo , Encéfalo/patologia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo
14.
Am J Hum Genet ; 98(4): 782-8, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040691

RESUMO

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.


Assuntos
Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Alelos , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Feminino , Variação Genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Hipotonia Muscular/diagnóstico , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
15.
Am J Hum Genet ; 98(3): 541-552, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942287

RESUMO

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Transposases/genética , Adolescente , Adulto , Animais , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Regulação para Baixo , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Exoma , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Modelos Lineares , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Mol Autism ; 7: 1, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26753090

RESUMO

BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic.


Assuntos
Células-Tronco Adultas/metabolismo , Transtorno do Espectro Autista/genética , MicroRNAs/genética , Mucosa Olfatória/patologia , Regiões 3' não Traduzidas/genética , Adulto , Animais , Astrócitos/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Vetores Genéticos/genética , Hipocampo/citologia , Hipocampo/embriologia , Humanos , Lentivirus/genética , Masculino , Camundongos , MicroRNAs/fisiologia , Neurônios/metabolismo , Neurônios/ultraestrutura , Especificidade de Órgãos , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Adulto Jovem
17.
Neurogenetics ; 17(1): 71-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26626498

RESUMO

Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.


Assuntos
Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Adulto , Argélia , Códon sem Sentido , Consanguinidade , Análise Mutacional de DNA , Família , Feminino , Efeito Fundador , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
Eur J Hum Genet ; 24(3): 455-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26153217

RESUMO

Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly.


Assuntos
Cerebelo/patologia , Códon sem Sentido/genética , Corpo Caloso/patologia , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Adolescente , Atrofia , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual/complicações , Masculino , Megalencefalia/complicações , Dados de Sequência Molecular , Linhagem
19.
Nat Neurosci ; 18(12): 1731-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26571461

RESUMO

The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.


Assuntos
Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação/genética , Inibição Neural/genética , Proteínas Associadas à Matriz Nuclear/genética , Fatores de Transcrição de Octâmero/genética , Proteínas de Ligação a RNA/genética , Sinapses/genética , Adolescente , Animais , Encéfalo/patologia , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linhagem , Sinapses/patologia
20.
Mol Genet Genomic Med ; 3(3): 215-20, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26029708

RESUMO

We investigated two siblings, born to consanguineous parents, with neurological features reminiscent of adaptor protein complex 4 (AP4) deficiency, an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity, severe intellectual disability speech delay, microcephaly, and growth retardation. Yet, both children also presented with early onset obesity. Whole-exome sequencing identified two homozygous substitutions in two genes 170 kb apart on 7q22.1: a c.1137+1G>T splice mutation in AP4M1 previously described in a familial case of AP4-deficiency syndrome and the AZGP1 c.595A>T missense variant. Haplotyping analysis indicated a founder effect of the AP4M1 mutation, whereas the AZGP1 mutation arose more recently in our family. AZGP1 encodes an adipokine that stimulate lipolysis in adipocytes and regulates body weight in mice. We propose that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Contiguous gene syndromes are the consequence of loss of two or more adjacent genes sensible to gene dosage and the phenotype reflects a combination of endophenotypes. We propose to broaden this concept to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutation syndrome.

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