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1.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
2.
Am J Med Genet B Neuropsychiatr Genet ; 177(8): 736-745, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30421579

RESUMO

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

3.
J Child Neurol ; 32(3): 271-285, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27920266

RESUMO

To describe pontine axonal anomalies across diverse brain malformations. Institutional review board-approved review of magnetic resonance imaging (MRI) and genetic testing of 31 children with brain malformations and abnormal pons by diffusion tensor imaging. Anomalous dorsal pontocerebellar tracts were seen in mid-hindbrain anomalies and in diffuse malformations of cortical development including lissencephaly, gyral disorganization with dysplastic basal ganglia, presumed congenital fibrosis of extraocular muscles type 3, and in callosal agenesis without malformations of cortical development. Heterotopic and hypoplastic corticospinal tracts were seen in callosal agenesis and in focal malformations of cortical development. There were no patterns by chromosomal microarray analysis in the non-lissencephalic brains. In lissencephaly, there was no relationship between severity, deletion size, or appearance of the pontocerebellar tract. Pontine axonal anomalies may relate to defects in precerebellar neuronal migration, chemotactic signaling of the pontine neurons, and/or corticospinal tract pathfinding and collateral branching not detectable with routine genetic testing.


Assuntos
Cerebelo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Ponte/diagnóstico por imagem , Pré-Escolar , Imagem de Tensor de Difusão , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Malformações do Sistema Nervoso/genética , Vias Neurais/diagnóstico por imagem
4.
Nat Neurosci ; 19(11): 1506-1512, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27668390

RESUMO

Class I histone deacetylases (HDACs) Hdac1 and Hdac2 can associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined whether Hdac1 and Hdac2 were functionally redundant in mature mouse brain. We demonstrate that postnatal forebrain-specific deletion of both Hdac1 and Hdac2 in mice impacts neuronal survival and results in an excessive grooming phenotype caused by dysregulation of Sap90/Psd95-associated protein 3 (Sapap3; also known as Dlgap3) in striatum. Moreover, Hdac1- and Hdac2-dependent regulation of Sapap3 expression requires MECP2, the gene involved in the pathophysiology of Rett syndrome. We show that postnatal forebrain-specific deletion of Mecp2 causes excessive grooming, which is rescued by restoring striatal Sapap3 expression. Our results provide new insight into the upstream regulation of Sapap3 and establish the essential role of striatal Hdac1, Hdac2 and MeCP2 for suppression of repetitive behaviors.


Assuntos
Corpo Estriado/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Animais , Comportamento Animal/fisiologia , Sistema Nervoso Central/metabolismo , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Fenótipo
5.
Nature ; 515(7526): 209-15, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25363760

RESUMO

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Cromatina/genética , Predisposição Genética para Doença/genética , Mutação/genética , Sinapses/metabolismo , Transcrição Genética/genética , Sequência de Aminoácidos , Transtornos Globais do Desenvolvimento Infantil/patologia , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Exoma/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Rede Nervosa/metabolismo , Razão de Chances
6.
Annu Rev Genomics Hum Genet ; 15: 195-213, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25184530

RESUMO

Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.


Assuntos
Córtex Cerebral/patologia , Transtornos Globais do Desenvolvimento Infantil/genética , Malformações do Desenvolvimento Cortical/genética , Neurônios/patologia , Alelos , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Criança , Transtornos Globais do Desenvolvimento Infantil/patologia , Citoesqueleto/genética , Citoesqueleto/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Dedos/anormalidades , Dedos/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Malformações do Desenvolvimento Cortical/patologia , Microcefalia/genética , Microcefalia/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Miopia/genética , Miopia/patologia , Neurônios/metabolismo , Obesidade/genética , Obesidade/patologia , Degeneração Retiniana
7.
Elife ; 32014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24970834

RESUMO

Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/genética , Alelos , Animais , Análise por Conglomerados , Ilhas de CpG , Modelos Animais de Doenças , Genes Dominantes , Genótipo , Humanos , Camundongos , Camundongos Transgênicos , Fenótipo , Mutação Puntual , Estrutura Terciária de Proteína
8.
Neuron ; 77(2): 259-73, 2013 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-23352163

RESUMO

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Animais , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Linhagem , Ratos , Análise de Sequência de DNA/métodos , Adulto Jovem
9.
PLoS Genet ; 8(4): e1002635, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22511880

RESUMO

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.


Assuntos
Transtorno Autístico/genética , Éxons , Genes Recessivos , Mutação , Neurônios , Proteínas Adaptadoras de Transdução de Sinal/genética , Cadeias Pesadas de Clatrina/genética , Éxons/genética , Genoma Humano , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Fatores de Transcrição Kruppel-Like/genética , Neurônios/metabolismo , Neurônios/fisiologia , Proteínas Oncogênicas/genética , Transcrição Genética , Ubiquitina-Proteína Ligases/genética
10.
J Mol Med (Berl) ; 84(3): 226-31, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16389551

RESUMO

To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212 -2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.


Assuntos
Genes Recessivos , Variação Genética , Perda Auditiva/genética , Proteínas de Membrana/genética , Conexinas , Frequência do Gene , Ligação Genética , Humanos , Jordânia , Paquistão , Linhagem , Polimorfismo Genético
11.
Hum Genet ; 118(5): 605-10, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16261342

RESUMO

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. Autosomal recessive (AR) forms of prelingual HI account for approximately 75% of cases with a genetic etiology. A novel AR non-syndromic HI locus (DFNB47) was mapped to chromosome 2p25.1-p24.3, in two distantly related Pakistani kindreds. Genome scan and fine mapping were carried out using microsatellite markers. Multipoint linkage analysis resulted in a maximum LOD score of 4.7 at markers D2S1400 and D2S262. The three-unit support interval was bounded by D2S330 and D2S131. The region of homozygosity was found within the three-unit support interval and flanked by markers D2S2952 and D2S131, which corresponds to 13.2 cM according to the Rutgers combined linkage-physical map. This region contains 5.3 Mb according to the sequence-based physical map. Three candidate genes, KCNF1, ID2 and ATP6V1C2 were sequenced, and were found to be negative for functional sequence variants.


Assuntos
Cromossomos Humanos Par 2 , Genes Recessivos , Perda Auditiva/genética , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Linhagem
12.
Hum Mutat ; 26(4): 396, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16134132

RESUMO

Though many hearing impairment genes have been identified, only a few of these genes have been screened in population studies. For this study, 168 Pakistani families with autosomal recessive hearing impairment not due to mutations in the GJB2 (Cx26) gene underwent a genome scan. Two-point and multipoint parametric linkage analyses were carried out. Twelve families had two-point or multipoint LOD scores of 1.4 or greater within the transmembrane cochlear expressed gene 1 (TMC1) region and were subjected to further screening with direct DNA sequencing. Five novel putatively functional non-synonymous sequence variants, c.830A>G (p.Y277C), c.1114G>A (p.V372M), c.1334G>A (p.R445H), c.2004T>G (p.S668R), and c.2035G>A (p.E679K), were found to segregate within seven families, but were not observed in 234 Pakistani control chromosomes. The variants c.830A>G (p.Y277C), c.1114G>A (p.V372M), and c.1334G>A (p.R445H) occurred at highly conserved regions and were predicted to lie within hydrophobic transmembrane domains, while non-synonymous variants c.2004T>G (p.S668R) and c.2035G>A (p.E679K) occurred in extracellular regions that were not highly conserved. There is evidence that the c.2004T>G (p.S668R) variant may have occurred at a phosphorylation site. One family has the known splice site mutation c.536 -8T>A. The prevalence of non-syndromic hearing impairment due to TMC1 in this Pakistani population is 4.4% (95%CI: 1.9, 8.6%). The TMC1 protein might have an important function in K(+) channels of inner hair cells, which would be consistent with the hypothetical structure of protein domains in which sequence variants were identified.


Assuntos
Genes Recessivos , Variação Genética , Perda Auditiva/genética , Proteínas de Membrana/genética , Conexinas , Consanguinidade , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Mutação , Paquistão , Análise de Sequência de Proteína
13.
Am J Med Genet A ; 133A(1): 18-22, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15641023

RESUMO

A consanguineous family with autosomal recessive nonsyndromic hearing impairment (NSHI) was ascertained in Pakistan and displayed significant evidence of linkage to 3q13.31-q22.3. The novel locus (DFNB42) segregating in this kindred, maps to a 21.6 cM region according to a genetic map constructed using data from both the deCode and Marshfield genetic maps. This region of homozygosity is flanked by markers D3S1278 and D3S2453. A maximum multipoint LOD score of 3.72 was obtained at marker D3S4523. DFNB42 represents the third autosomal recessive NSHI locus to map to chromosome 3.


Assuntos
Cromossomos Humanos Par 3/genética , Genes Recessivos/genética , Perda Auditiva/genética , Audiometria , Mapeamento Cromossômico , Feminino , Ligação Genética , Predisposição Genética para Doença/genética , Genótipo , Perda Auditiva/patologia , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem
14.
Am J Med Genet A ; 133A(1): 23-6, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15637723

RESUMO

Hereditary nonsyndromic deafness (NSD) is extremely heterogeneous. Autosomal recessive (AR) forms account for approximately 75% of genetic cases. To date, over 40 ARNSD loci have been mapped. A novel locus (DFNB46) for ARNSD was mapped to chromosome 18p11.32-p11.31 in a five-generation Pakistani family. A 10 cM genome-wide scan and fine mapping was carried out using microsatellite markers. A maximum multipoint LOD score of 3.8 was obtained at two markers, D18S481 and D18S1370. The three-unit support interval is flanked by markers D18S59 and D18S391, corresponds to a 17.6 cM region according to the deCode genetic map and spans 5.8 Mb on the sequence-based physical map.


Assuntos
Cromossomos Humanos Par 18/genética , Surdez/genética , Genes Recessivos/genética , Mapeamento Cromossômico , Surdez/patologia , Feminino , Ligação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem
15.
Hum Hered ; 57(4): 195-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15583425

RESUMO

The genetic etiology for many forms of hearing impairment (HI) is very diverse. Non-syndromic HI (NSHI) is one of the most heterogeneous traits known. Autosomal recessive forms of prelingual HI account for approximately 75% of hereditary cases. A novel autosomal recessive NSHI locus, DFNB44, was mapped to a 20.9 cM genetic interval on chromosome 7p14.1-q11.22, according to the Marshfield genetic map, in a consanguineous Pakistani family. Multipoint linkage analysis resulted in a maximum LOD score of 5.0 at marker D7S1818. The 3-unit support interval ranged from marker D7S2209 to marker D7S2435, spanning a 30.1 Mb region on the sequence-based physical map.


Assuntos
Cromossomos Humanos Par 7 , Genes Recessivos , Perda Auditiva/genética , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Linhagem
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