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Nat Commun ; 9(1): 4250, 2018 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-30315159

RESUMEN

Germline mutations in the ubiquitously expressed ACTB, which encodes ß-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we demonstrate cohort specific changes to ß-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs). These perturbed interactions are supported by in silico modeling and are validated in disease-relevant thrombocytes. Co-examination of actin and microtubule cytoskeleton constituents in patient-derived megakaryocytes and thrombocytes indicates that these ß-CYA mutations inhibit the final stages of platelet maturation by compromising microtubule organization. Our results define an ACTB-associated clinical syndrome with a distinct genotype-phenotype correlation and delineate molecular mechanisms underlying thrombocytopenia in this patient cohort.


Asunto(s)
Actinas/genética , Exones/genética , Trombocitopenia/genética , Actinas/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Citoesqueleto/metabolismo , Femenino , Genotipo , Mutación de Línea Germinal/genética , Humanos , Masculino , Megacariocitos/metabolismo , Mutación/genética , Fenotipo , Trombocitopenia/metabolismo
3.
Int J Med Microbiol ; 305(8): 874-80, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26358917

RESUMEN

Recently, we identified a putative prophage on a genomic island (GI) within the genome sequence of Francisella hispaniensis isolate AS0-814 (Francisella tularensis subsp. novicida-like 3523) by the analysis of the CRISPR-Cas systems of Francisella. Various spacer DNAs within the CRISPR region of different F. tularensis subsp. novicida strains were found to be homologous to the putative prophage (Schunder et al., 2013, Int. J. Med. Microbiol. 303:51-60). Now we identified the GI (FhaGI-1) as a mobile element which is able to form a circular episomal structure. The circular episomal form of FhaGI-1 is generated by F. hispaniensis, and the excision of the island is an integrase-dependent and site-specific process. Furthermore, we could demonstrate that the excision of the island is also possible in other bacterial species (Escherichia coli). In addition, we could show that a genetically generated small variant of the island is also functional and, after its electroporation into strain F. tularensis subsp. holarctica LVS, the GI was stable and site-specifically integrated into the genome of the transformants. The integrase is sufficient for the integration and excision of the small variant into and from the DNA backbone, respectively. Thus, the element may be suitable to be used as a genetic tool in F. tularensis research. Furthermore, we identified the tRNA(Val) gene of Francisella as an integration site for GIs. Genomic island FphGI-1 was identified in Francisella philomiragia ATCC 25016. We were not able to detect the episomal form of this GI, probably due to a mutated attR site. However, we could demonstrate that integrative GIs are present in Francisella and that they may allow horizontal gene transfer between different Francisella species.


Asunto(s)
Francisella/genética , Islas Genómicas , Plásmidos , Escherichia coli/genética , Integrasas/genética , Integrasas/metabolismo , Secuencias Repetitivas Esparcidas , Profagos/genética , ARN de Transferencia de Valina/genética , Recombinación Genética
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