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1.
Clin Genet ; 95(1): 177-181, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30298622

RESUMO

Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.


Assuntos
Vestibulopatia Bilateral/genética , Surdez/genética , Proteínas de Membrana/genética , Transtornos Motores/genética , Animais , Vestibulopatia Bilateral/diagnóstico por imagem , Vestibulopatia Bilateral/fisiopatologia , Surdez/diagnóstico por imagem , Surdez/fisiopatologia , Eletrorretinografia , Feminino , Mutação da Fase de Leitura/genética , Homozigoto , Humanos , Lactente , Masculino , Camundongos , Transtornos Motores/diagnóstico por imagem , Transtornos Motores/fisiopatologia , Linhagem , Tomografia Computadorizada por Raios X , Sequenciamento do Exoma
2.
Hum Mutat ; 35(1): 137-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24166846

RESUMO

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.


Assuntos
Doenças Cerebelares/genética , Doenças Cerebelares/metabolismo , Cílios/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Retina/anormalidades , Fatores de Ribosilação do ADP/metabolismo , Anormalidades Múltiplas , Animais , Cerebelo/anormalidades , Exoma , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Modelos Moleculares , Linhagem , Prenilação de Proteína , Proteômica , Retina/metabolismo , Análise de Sequência de DNA , Peixe-Zebra/anormalidades , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
J Med Genet ; 49(11): 713-20, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23125460

RESUMO

BACKGROUND: Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. METHODS: We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. RESULTS: Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. CONCLUSIONS: These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS.


Assuntos
Síndrome Acrocalosal/genética , Cinesinas/genética , Mutação , Síndrome Acrocalosal/diagnóstico , Síndrome Acrocalosal/fisiopatologia , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/fisiopatologia , Pré-Escolar , Feminino , Feto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polidactilia/diagnóstico , Polidactilia/fisiopatologia
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