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1.
J Med Genet ; 52(3): 147-56, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25564561

RESUMO

BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. METHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.


Assuntos
Proteínas Cromossômicas não Histona/genética , Cílios/genética , Genética Médica , Microcefalia/genética , Proteínas dos Microfilamentos/genética , Animais , Centríolos/genética , Cílios/patologia , Exoma/genética , Feminino , Feto , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Microcefalia/patologia , Mutação , Células NIH 3T3 , Linhagem , Gravidez , Peixe-Zebra
2.
Hum Mutat ; 32(8): 930-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21542058

RESUMO

Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities.


Assuntos
Efrina-B1/genética , Duplicação Gênica/genética , Hipertelorismo/genética , Adulto , Alelos , Animais , Sequência de Bases , Criança , Cromossomos Humanos X/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Hipertelorismo/diagnóstico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Fenótipo , Alinhamento de Sequência , Transcrição Gênica , Inativação do Cromossomo X
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