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1.
J Med Genet ; 59(4): 358-365, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33820834

RESUMO

BACKGROUND: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. METHODS: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. RESULTS: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. CONCLUSION: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.


Assuntos
Holoprosencefalia , Fosfolipases Tipo C , Animais , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Holoprosencefalia/metabolismo , Humanos , Mamíferos/metabolismo , Mutação , Fenótipo , Fosfolipases Tipo C/genética
2.
Hum Mol Genet ; 26(3): 519-526, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053047

RESUMO

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.


Assuntos
Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Transtorno Autístico/patologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade , Quinases Dyrk
3.
Trends Genet ; 27(8): 307-15, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21680046

RESUMO

Centrioles are microtubule-derived structures that are essential for the formation of centrosomes, cilia and flagella. The centrosome is the major microtubule organiser in animal cells, participating in a variety of processes, from cell polarisation to cell division, whereas cilia and flagella contribute to several mechanisms in eukaryotic cells, from motility to sensing. Although it was suggested more than a century ago that these microtubule-derived structures are involved in human disease, the molecular bases of this association have only recently been discovered. Surprisingly, there is very little overlap between the genes affected in the different diseases, suggesting that there are tissue-specific requirements for these microtubule-derived structures. Knowledge of these requirements and disease mechanisms has opened new avenues for therapeutical strategies. Here, we give an overview of recent developments in this field, focusing on cancer, diseases of brain development and ciliopathies.


Assuntos
Centrossomo/fisiologia , Cílios/fisiologia , Microcefalia/patologia , Neoplasias/patologia , Aneuploidia , Divisão Celular , Instabilidade Cromossômica , Humanos , Doenças Renais Císticas/patologia , Mutação , Transdução de Sinais , Fuso Acromático/fisiologia
4.
Elife ; 112022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36421765

RESUMO

EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease, but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58 kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions, and P2X7 is almost absent in EROS-deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation, and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation, and possibly gene therapy.


Assuntos
Doença Granulomatosa Crônica , NADPH Oxidases , Humanos , Animais , Camundongos , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fagócitos/metabolismo , Transdução de Sinais/fisiologia
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