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1.
Am J Hum Genet ; 105(5): 987-995, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587868

RESUMO

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

2.
Am J Hum Genet ; 105(4): 844-853, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585108

RESUMO

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

5.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

7.
Brain Dev ; 40(5): 429-432, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29428275

RESUMO

PURPOSE: A recurrent de novo mutation in KCNC1 (c.959G > A, p.Arg320His) has been identified recently as one of the important genetic causes of progress myoclonic epilepsy (PME). The clinical phenotype resulting from this mutation has been named as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). This finding carries important clinical implications in that autosomal dominant inheritance and de novo occurrence need to be considered when conducting genetic tests in patients with PME. We present two familial cases of MEAK in siblings with a recurrent p.Arg320His mutation in KCNC1. METHOD: Whole exome sequencing and subsequent Sanger sequencing were performed for the cases and their parents. RESULTS: A recurrent p.Arg320His mutation in KCNC1 was identified in the two brothers who showed characteristic features of MEAK: near normal early development, onset of myoclonus around 10 years of age, infrequent generalized tonic-clonic seizures, relatively mild cognitive impairment, and generalized epileptiform discharges. Interestingly, the asymptomatic mother was suspected as being mosaic for this mutation. This finding could lead to misleading inheritance patterns and make genetic diagnosis of PME more complicated. CONCLUSIONS: Our familial MEAK cases show that consideration of parental mosaicism in addition to meticulous phenotyping is needed when conducting KCNC1 genetic testing.


Assuntos
Epilepsias Mioclônicas/genética , Canais de Potássio Shaw/genética , Adulto , Ataxia/genética , Criança , Família , Feminino , Humanos , Masculino , Mosaicismo , Mutação , Epilepsias Mioclônicas Progressivas/genética , Linhagem , Fenótipo , Canais de Potássio/genética , Convulsões/genética , Canais de Potássio Shaw/metabolismo , Irmãos
9.
Brain Dev ; 40(5): 383-390, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29439846

RESUMO

BACKGROUND: GM1 gangliosidosis is a rare lysosomal storage disorder caused by GLB1 mutations. Because of its extreme rarity and symptoms that overlap with other neurodegenerative diseases, its diagnosis is sometimes challenging, especially in the late infantile form with less severe phenotype. We aim to expand the clinical and genetic spectrum of late infantile GM1 gangliosidosis. METHODS: We confirmed a diagnosis of GM1 gangliosidosis based on GLB1 mutations and/or the deficiency of ß-galactosidase activity. We identified the first two cases by whole-exome sequencing, and then the other six cases by direct sequencing of GLB1 with enzyme analysis. RESULTS: All eight patients presented with developmental delay or regression during late infancy and later developed epilepsy, mostly intractable generalized tonic seizures. No clinical signs of storage disorders were noted except for skeletal abnormalities. Interestingly, we found aspartate transaminase (AST) elevations alone with normal alanine transaminase (ALT) levels in all patients. The recurrent mutation, p.D448V in GLB1, accounted for 50.0% of total alleles in our cohort. CONCLUSIONS: With a high index of clinical suspicion, skeletal survey and AST level would be important for early diagnosis of GM1 gangliosidosis. In addition, we would highlight the clinical usefulness of whole-exome sequencing in the diagnosis of non-classical presentation of ultra-rare neurodegenerative disease in children.


Assuntos
Gangliosidose GM1/diagnóstico , Gangliosidose GM1/genética , beta-Galactosidase/genética , Alelos , Aspartato Aminotransferases/metabolismo , Feminino , Gangliosidose GM1/enzimologia , Humanos , Lactente , Doenças por Armazenamento dos Lisossomos/diagnóstico , Masculino , Mutação , Substância Branca/fisiopatologia , Sequenciamento Completo do Exoma/métodos , beta-Galactosidase/metabolismo , beta-Galactosidase/fisiologia
10.
IEEE Trans Neural Netw Learn Syst ; 29(1): 118-128, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28113785

RESUMO

This paper considers nonfragile exponential synchronization for complex dynamical networks (CDNs) with time-varying coupling delay. The sampled-data feedback control, which is assumed to allow norm-bounded uncertainty and involves a constant signal transmission delay, is constructed for the first time in this paper. By constructing a suitable augmented Lyapunov function, and with the help of introduced integral inequalities and employing the convex combination technique, a sufficient condition is developed, such that the nonfragile exponential stability of the error system is guaranteed. As a result, for the case of sampled-data control free of norm-bound uncertainties, some sufficient conditions of sampled-data synchronization criteria for the CDNs with time-varying coupling delay are presented. As the formulations are in the framework of linear matrix inequality, these conditions can be easily solved and implemented. Two illustrative examples are presented to demonstrate the effectiveness and merits of the proposed feedback control.

11.
Exp Mol Med ; 49(12): e414, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29244787

RESUMO

Many cellular structures directly imply specific biological functions. For example, normal slit diaphragm structures that extend from podocyte foot processes ensure the filtering function of renal glomeruli. These slits are covered by a number of surface proteins, such as nephrin, podocin, podocalyxin and CD2AP. Here we report a human patient presenting with congenital nephrotic syndrome, omphalocele and microcoria due to two loss-of-function mutations in PODXL, which encodes podocalyxin, inherited from each parent. This set of symptoms strikingly mimics previously reported mouse Podxl-/- embryos, emphasizing the essential function of PODXL in mammalian kidney development and highlighting this patient as a human PODXL-null model. The results underscore the utility of current genomics approaches to provide insights into the genetic mechanisms of human disease traits through molecular diagnosis.


Assuntos
Proteínas de Membrana/genética , Síndrome Nefrótica/genética , Podócitos/metabolismo , Sialoglicoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Glomérulos Renais/metabolismo , Camundongos , Mutação , Síndrome Nefrótica/patologia , Podócitos/patologia
12.
Sci Rep ; 7(1): 4287, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28655895

RESUMO

Despite efforts to interrogate human genome variation through large-scale databases, systematic preference toward populations of Caucasian descendants has resulted in unintended reduction of power in studying non-Caucasians. Here we report a compilation of coding variants from 1,055 healthy Korean individuals (KOVA; Korean Variant Archive). The samples were sequenced to a mean depth of 75x, yielding 101 singleton variants per individual. Population genetics analysis demonstrates that the Korean population is a distinct ethnic group comparable to other discrete ethnic groups in Africa and Europe, providing a rationale for such independent genomic datasets. Indeed, KOVA conferred 22.8% increased variant filtering power in addition to Exome Aggregation Consortium (ExAC) when used on Korean exomes. Functional assessment of nonsynonymous variant supported the presence of purifying selection in Koreans. Analysis of copy number variants detected 5.2 deletions and 10.3 amplifications per individual with an increased fraction of novel variants among smaller and rarer copy number variable segments. We also report a list of germline variants that are associated with increased tumor susceptibility. This catalog can function as a critical addition to the pre-existing variant databases in pursuing genetic studies of Korean individuals.

13.
Eur J Paediatr Neurol ; 21(2): 404-409, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28041799

RESUMO

BACKGROUND: Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy. CASE PRESENTATION: The index case had a history of hepatomegaly and intermittent vomiting after upper respiratory infection at 11 months of age. Her older brothers had died at an early age, one with similar symptoms and the other because of septic shock. Her older sister had similar presenting symptoms; she later suffered from both cataracts and primary amenorrhea, but showed neurological improvement. Her follow-up MRIs (at 21 years of age) revealed progressive diffuse brain atrophy with leukoencephalopathy, without cystic rarefaction. Whole-exome sequencing of the index case revealed the presence of the compound heterozygous variants, Val85Glu and Met226Lys in EIF2B2. The affected sister had the same compound heterozygous variants, and their unaffected parents were heterozygous carriers of each variant. CONCLUSIONS: This study expanded the clinical and genetic spectrum of VWM with EIF2B2 variants. It would be better to consider VWM as an eIF2B-related multisystem disorder, not just as a neurological disorder, on the basis that this is a family of housekeeping genes that affect multiple organs.


Assuntos
Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/genética , Adolescente , Pré-Escolar , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Linhagem , Irmãos
14.
Genomics Inform ; 14(2): 42-5, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27445646

RESUMO

Since next-generation sequencing (NGS) technique was adopted into clinical practices, revolutionary advances in diagnosing rare genetic diseases have been achieved through translating genomic medicine into precision or personalized management. Indeed, several successful cases of molecular diagnosis and treatment with personalized or targeted therapies of rare genetic diseases have been reported. Still, there are several obstacles to be overcome for wider application of NGS-based precision medicine, including high sequencing cost, incomplete variant sensitivity and accuracy, practical complexities, and a shortage of available treatment options.

15.
Am J Med Genet A ; 170(11): 3023-3027, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27411168

RESUMO

Farber disease is a very rare autosomal recessive disease caused by mutation of ASAH1 that results in the accumulation of ceramide in various tissues. Clinical symptoms of classic Farber disease comprise painful joint deformity, hoarseness of voice, and subcutaneous nodules. Here, we describe a patient with Farber disease with atypical presentation of early onset hypotonia, sacral mass, congenital heart disease, and dysmorphic face since birth. Severe cognitive disability, failure to gain motor skills, failure to thrive, and joint contractures developed. Using whole-exome sequencing, we identified the compound heterozygote missense mutations of ASAH1 (p.R333C and p.G235R). Because of the diagnostic delay, she underwent sacral mass excision, which revealed enlarged lysosomes and zebra bodies. We report an atypical presentation of Farber disease with her pathology and associated genetic defect. This case expands the phenotypic spectrum of Farber disease to include novel mutations of ASAH1, which pose a diagnostic challenge. We also discuss the clinical utility of whole-exome sequencing for diagnosis of ultra-rare diseases. © 2016 Wiley Periodicals, Inc.


Assuntos
Ceramidase Ácida/genética , Lipogranulomatose de Farber/diagnóstico , Lipogranulomatose de Farber/genética , Mutação , Fenótipo , Idade de Início , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Encéfalo/patologia , Análise Mutacional de DNA , Exoma , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Linhagem
16.
J Am Soc Nephrol ; 27(11): 3430-3439, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27068226

RESUMO

TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.


Assuntos
Glomerulonefrite por IGA/complicações , Falência Renal Crônica/etiologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Adulto , Linfócitos B/fisiologia , Progressão da Doença , Feminino , Humanos , Masculino , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue
18.
Gene ; 569(2): 318-22, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25936994

RESUMO

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is a genetic syndrome caused by mutation of the ATRX gene associated with chromatin remodeling. Recently, a wide spectrum of brain MRI abnormalities and clinical manifestations has been recognized. We describe two male patients with genetically confirmed ATRX syndrome, both presented with developmental delay and white matter changes without typical clinical characteristics of ATRX. Whole-exome sequencing revealed the presence of ATRX mutations: a novel c.6472A>G mutation in Case 1 and a previously reported c.6532C>T mutation in Case 2. These two cases expanded the genetic and clinical spectrum of ATRX syndrome, including brain MRI abnormalities. Our results suggest that male patients with developmental delay and widespread white matter changes, even without distinctive facial dysmorphism and hematologic abnormalities, should be suspected as ATRX syndrome. We support the clinical utility of whole-exome sequencing, particularly in ultra-rare neurological diseases with nonspecific developmental disabilities and atypical presentation.


Assuntos
DNA Helicases/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas Nucleares/genética , Talassemia alfa/genética , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , DNA Helicases/química , Exoma , Humanos , Lactente , Masculino , Retardo Mental Ligado ao Cromossomo X/patologia , Dados de Sequência Molecular , Proteínas Nucleares/química , Alinhamento de Sequência , Proteína Nuclear Ligada ao X , Talassemia alfa/patologia
19.
IEEE Trans Neural Netw Learn Syst ; 25(10): 1936-41, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25291745

RESUMO

In this brief, an extended dissipativity analysis was conducted for a neural network with time-varying delays. The concept of the extended dissipativity can be used to solve for the H∞, L2-L∞, passive, and dissipative performance by adjusting the weighting matrices in a new performance index. In addition, the activation function dividing method is modified by introducing a tuning parameter. Examples are provided to show the effectiveness and less conservatism of the proposed method.


Assuntos
Redes Neurais (Computação) , Dinâmica não Linear , Reconhecimento Automatizado de Padrão/métodos , Algoritmos , Simulação por Computador , Humanos , Fatores de Tempo
20.
J AAPOS ; 18(2): 159-61, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24698614

RESUMO

PURPOSE: To evaluate the clinical characteristics and treatment outcomes of patients with congenital membranous punctal obstruction. METHODS: The medical records of patients who underwent surgical treatment for congenital membranous punctal obstruction between 1999 and 2011 were retrospectively reviewed. The demographic data and clinical presentations of the patients were analyzed. Surgical intervention methods and treatment results were also evaluated. RESULTS: A total of 51 puncta in 31 eyes of 23 patients with congenital membranous punctal obstruction were included. Of the 31 eyes, 20 had both upper and lower punctal obstruction and 11 had single punctal obstruction. Up to 2008, 10 patients underwent simultaneous punctoplasty and silicone tube intubation; 7 were under 10 years of age and required general anesthesia for the procedure. All showed patent puncta without epiphora postoperatively. Of the 13 patients treated after 2008, 11 children underwent punctoplasty and lacrimal irrigation under general anesthesia. Nasolacrimal duct obstruction (NLDO) was found in 6 of the 11 patients, and combined silicone tube intubation was performed; 2 adults with both upper and lower punctal obstruction underwent only punctoplasty under local anesthesia. All puncta were opened sufficiently, but epiphora remained in 1 patient due to NLDO, requiring subsequent silicone intubation. Overall, NLDO was found in 7 of 13 patients. CONCLUSIONS: Congenital membranous punctal obstruction can be successfully treated by punctoplasty alone. Because this is often associated with NLDO, the nasolacrimal system should also be thoroughly evaluated.


Assuntos
Dacriocistorinostomia/métodos , Pálpebras/cirurgia , Ducto Nasolacrimal/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Pálpebras/patologia , Feminino , Humanos , Intubação , Obstrução dos Ductos Lacrimais/congênito , Obstrução dos Ductos Lacrimais/diagnóstico , Masculino , Membranas , Ducto Nasolacrimal/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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