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1.
Nat Commun ; 14(1): 5574, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37696869

RESUMO

Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identify twelve loci, of which four are novel ([Formula: see text]). Substantial genetic sharing between PCV and typical nAMD is noted (rg = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; [Formula: see text]) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population.


Assuntos
Degeneração Macular , Vasculopatia Polipoidal da Coroide , Idoso , Animais , Humanos , Camundongos , Asiático , População do Leste Asiático , Matriz Extracelular/genética , Estudo de Associação Genômica Ampla , Degeneração Macular/genética , Vasculopatia Polipoidal da Coroide/genética , Modelos Animais de Doenças
2.
Nat Commun ; 10(1): 4307, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541088

RESUMO

To facilitate proper mitotic cell partitioning, the Golgi disassembles by suppressing vesicle fusion. However, the underlying mechanism has not been characterized previously. Here, we report a Ran pathway-independent attenuation mechanism that allows Importin-α (a nuclear transport factor) to suppress the vesicle fusion mediated by p115 (a vesicular tethering factor) and is required for mitotic Golgi disassembly. We demonstrate that Importin-α directly competes with p115 for interaction with the Golgi protein GM130. This interaction, promoted by a phosphate moiety on GM130, is independent of Importin-ß and Ran. A GM130 K34A mutant, in which the Importin-α-GM130 interaction is specifically disrupted, exhibited abundant Golgi puncta during metaphase. Importantly, a mutant showing enhanced p115-GM130 interaction presented proliferative defects and G2/M arrest, demonstrating that Importin-α-GM130 binding modulates the Golgi disassembly that governs mitotic progression. Our findings illuminate that the Ran and kinase-phosphatase pathways regulate multiple aspects of mitosis coordinated by Importin-α (e.g. spindle assembly, Golgi disassembly).


Assuntos
Autoantígenos/metabolismo , Complexo de Golgi/metabolismo , Proteínas da Matriz do Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Metáfase/fisiologia , Proteínas de Transporte Vesicular/metabolismo , alfa Carioferinas/metabolismo , Autoantígenos/genética , Cristalografia por Raios X , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HEK293 , Humanos , Fusão de Membrana , Proteínas de Membrana/genética , Mitose/fisiologia , Fosforilação , Ligação Proteica , beta Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/metabolismo
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