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1.
Genes (Basel) ; 14(12)2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38137040

RESUMO

Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease.


Assuntos
Encefalopatias Metabólicas , Humanos , Encefalopatias Metabólicas/diagnóstico , Glutaril-CoA Desidrogenase , Fenótipo , Genótipo
2.
Mol Microbiol ; 116(3): 743-765, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34115422

RESUMO

Cyanobacteria synthesize type IV pili, which are known to be essential for motility, adhesion and natural competence. They consist of long flexible fibers that are primarily composed of the major pilin PilA1 in Synechocystis sp. PCC 6803. In addition, Synechocystis encodes less abundant pilin-like proteins, which are known as minor pilins. In this study, we show that the minor pilin PilA5 is essential for natural transformation but is dispensable for motility and flocculation. In contrast, a set of minor pilins encoded by the pilA9-slr2019 transcriptional unit are necessary for motility but are dispensable for natural transformation. Neither pilA5-pilA6 nor pilA9-slr2019 are essential for pilus assembly as mutant strains showed type IV pili on the cell surface. Three further gene products with similarity to PilX-like minor pilins have a function in flocculation of Synechocystis. The results of our study indicate that different minor pilins facilitate distinct pilus functions. Further, our microarray analysis demonstrated that the transcription levels of the minor pilin genes change in response to surface contact. A total of 122 genes were determined to have altered transcription between planktonic and surface growth, including several plasmid genes which are involved exopolysaccharide synthesis and the formation of bloom-like aggregates.


Assuntos
Fenômenos Fisiológicos Bacterianos , Proteínas de Fímbrias/fisiologia , Fímbrias Bacterianas/fisiologia , Synechocystis/fisiologia , Sequência de Aminoácidos , Proteínas de Bactérias/fisiologia , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Análise em Microsséries , Deleção de Sequência
3.
J Bacteriol ; 201(19)2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262837

RESUMO

Motile strains of the unicellular cyanobacterium Synechocystis sp. strain PCC 6803 readily aggregate into flocs, or floating multicellular assemblages, when grown in liquid culture. As described here, we used confocal imaging to probe the structure of these flocs, and we developed a quantitative assay for floc formation based on fluorescence imaging of 6-well plates. The flocs are formed from strands of linked cells, sometimes packed into dense clusters but also containing voids with very few cells. Cells within the dense clusters show signs of nutrient stress, as judged by the subcellular distribution of green fluorescent protein (GFP)-tagged Vipp1 protein. We analyzed the effects on flocculation of a series of mutations that alter piliation and motility, including Δhfq, ΔpilB1, ΔpilT1, and ΔushA mutations and deletion mutations affecting major and minor pilins. The extent of flocculation is increased in the hyperpiliated ΔpilT1 mutant, but active cycles of pilus extension and retraction are not required for flocculation. Deletion of PilA1, the major subunit of type IV pili, has no effect on flocculation; however, flocculation is lost in mutants lacking an operon coding for the minor pilins PilA9 to -11. Therefore, minor pilins appear crucial for flocculation. We show that flocculation is a tightly regulated process that is promoted by blue light perception by the cyanobacteriochrome Cph2. Floc formation also seems to be a highly cooperative process. A proportion of nonflocculating Δhfq cells can be incorporated into wild-type flocs, but the presence of a high proportion of Δhfq cells disrupts the large-scale architecture of the floc.IMPORTANCE Some bacteria form flocs, which are multicellular floating assemblages of many thousands of cells. Flocs have been relatively little studied compared to surface-adherent biofilms, but flocculation could play many physiological roles, be a crucial factor in marine carbon burial, and enable more efficient biotechnological cell harvesting. We studied floc formation and architecture in the model cyanobacterium Synechocystis sp. strain PCC 6803, using mutants to identify specific cell surface structures required for floc formation. We show that floc formation is regulated by blue and green light perceived by the photoreceptor Cph2. The flocs have a characteristic structure based on strands of linked cells aggregating into dense clusters. Cells within the dense clusters show signs of nutrient stress, pointing to a disadvantage of floc formation.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Membrana/metabolismo , Mutação , Synechocystis/crescimento & desenvolvimento , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Técnicas Bacteriológicas , Fímbrias Bacterianas/genética , Floculação , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Fator Proteico 1 do Hospedeiro/genética , Proteínas de Membrana/genética , Diester Fosfórico Hidrolases/genética , Proteínas Recombinantes/metabolismo , Synechocystis/genética , Synechocystis/metabolismo
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