Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Eur J Hum Genet ; 21(10): 1074-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23386033

RESUMO

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.


Assuntos
Doenças Cerebelares/genética , Anormalidades do Olho/genética , Frequência do Gene , Doenças Renais Císticas/genética , Mutação , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Retina/anormalidades , Anormalidades Múltiplas , Adolescente , Sequência de Aminoácidos , Doenças Cerebelares/diagnóstico , Cerebelo/anormalidades , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/genética , Encefalocele/diagnóstico , Encefalocele/genética , Anormalidades do Olho/diagnóstico , Feminino , Heterozigoto , Humanos , Lactente , Doenças Renais Císticas/diagnóstico , Masculino , Dados de Sequência Molecular , Linhagem , Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/genética , Diagnóstico Pré-Natal , Prevalência , Retinose Pigmentar
2.
Orphanet J Rare Dis ; 7: 4, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-22236771

RESUMO

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Doenças Cerebelares/classificação , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Anormalidades do Olho/classificação , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/classificação , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Síndromes Orofaciodigitais/classificação , Síndromes Orofaciodigitais/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/patologia , Retina/anormalidades , Retina/patologia , Adulto Jovem
3.
Science ; 335(6071): 966-9, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22282472

RESUMO

Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.


Assuntos
Doenças Cerebelares/genética , Cílios/ultraestrutura , Evolução Molecular , Anormalidades do Olho/genética , Regulação da Expressão Gênica , Loci Gênicos , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Sequências Reguladoras de Ácido Nucleico , Sequência de Aminoácidos , Animais , Linhagem Celular , Doenças Cerebelares/metabolismo , Doenças Cerebelares/patologia , Cílios/metabolismo , Sequência Conservada , DNA Intergênico , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Perfilação da Expressão Gênica , Heterogeneidade Genética , Humanos , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Família Multigênica , Mutação , Mutação de Sentido Incorreto , Fenótipo , Transporte Proteico , Retina/anormalidades , Retina/metabolismo , Retina/patologia , Vesículas Transportadoras/metabolismo , Vesículas Transportadoras/ultraestrutura
4.
Am J Hum Genet ; 87(2): 265-73, 2010 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-20691405

RESUMO

Ectodermal dysplasias form a large disease family with more than 200 members. The combination of hair and tooth abnormalities, alopecia, and cutaneous syndactyly is characteristic of ectodermal dysplasia-syndactyly syndrome (EDSS). We used a homozygosity mapping approach to map the EDSS locus to 1q23 in a consanguineous Algerian family. By candidate gene analysis, we identified a homozygous mutation in the PVRL4 gene that not only evoked an amino acid change but also led to exon skipping. In an Italian family with two siblings affected by EDSS, we further detected a missense and a frameshift mutation. PVRL4 encodes for nectin-4, a cell adhesion molecule mainly implicated in the formation of cadherin-based adherens junctions. We demonstrated high nectin-4 expression in hair follicle structures, as well as in the separating digits of murine embryos, the tissues mainly affected by the EDSS phenotype. In patient keratinocytes, mutated nectin-4 lost its capability to bind nectin-1. Additionally, in discrete structures of the hair follicle, we found alterations of the membrane localization of nectin-afadin and cadherin-catenin complexes, which are essential for adherens junction formation, and we found reorganization of actin cytoskeleton. Together with cleft lip and/or palate ectodermal dysplasia (CLPED1, or Zlotogora-Ogur syndrome) due to an impaired function of nectin-1, EDSS is the second known "nectinopathy" caused by mutations in a nectin adhesion molecule.


Assuntos
Moléculas de Adesão Celular/genética , Displasia Ectodérmica/complicações , Displasia Ectodérmica/genética , Mutação/genética , Sindactilia/complicações , Sindactilia/genética , Anormalidades Múltiplas/genética , Adulto , Sequência de Aminoácidos , Animais , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Criança , Extremidades/embriologia , Família , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Cabelo/patologia , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/patologia , Síndrome
5.
Nat Genet ; 42(7): 619-25, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20512146

RESUMO

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.


Assuntos
Anormalidades Múltiplas/genética , Cílios/patologia , Proteínas de Membrana/genética , Mutação , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Consanguinidade , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Gastrulação/genética , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hibridização In Situ , Judeus/genética , Microscopia Confocal , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Interferência de RNA , Síndrome , Peixe-Zebra/embriologia , Peixe-Zebra/genética
6.
Hum Mutat ; 31(5): E1319-31, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20232449

RESUMO

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.


Assuntos
Anormalidades Múltiplas/genética , Doenças Renais Císticas/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Mutação/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Doenças Renais Císticas/patologia , Cirrose Hepática/patologia , Fenótipo , Gravidez , Diagnóstico Pré-Natal
7.
Am J Med Genet A ; 149A(10): 2173-80, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19764032

RESUMO

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.


Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/genética , Cílios , Proteínas de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Sequência de Bases , Proteínas de Ciclo Celular , Cílios/genética , Cílios/patologia , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Feminino , Feto/metabolismo , Feto/patologia , Deleção de Genes , Testes Genéticos , Humanos , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/análise , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA