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[PMID]:28753627
[Au] Autor:Scott CA; Marsden AN; Rebagliati MR; Zhang Q; Chamling X; Searby CC; Baye LM; Sheffield VC; Slusarski DC
[Ad] Endereço:Department of Biology, University of Iowa, Iowa City, Iowa, United States of America.
[Ti] Título:Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein.
[So] Source:PLoS Genet;13(7):e1006936, 2017 Jul.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.
[Mh] Termos MeSH primário: Anormalidades Múltiplas/genética
Síndrome de Bardet-Biedl/genética
Chaperoninas do Grupo II/genética
Cardiopatias Congênitas/genética
Hidrocolpos/genética
Polidactilia/genética
Fatores de Transcrição/genética
Doenças Uterinas/genética
[Mh] Termos MeSH secundário: Anormalidades Múltiplas/metabolismo
Anormalidades Múltiplas/patologia
Transporte Ativo do Núcleo Celular/genética
Animais
Animais Geneticamente Modificados/genética
Síndrome de Bardet-Biedl/metabolismo
Síndrome de Bardet-Biedl/patologia
Cromatina/genética
Montagem e Desmontagem da Cromatina/genética
Cílios/metabolismo
Cílios/patologia
Citoplasma/metabolismo
Modelos Animais de Doenças
Cardiopatias Congênitas/metabolismo
Cardiopatias Congênitas/patologia
Seres Humanos
Hidrocolpos/metabolismo
Hidrocolpos/patologia
Camundongos
Mutação
Polidactilia/metabolismo
Polidactilia/patologia
Transporte Proteico/genética
Fatores de Transcrição/biossíntese
Doenças Uterinas/metabolismo
Doenças Uterinas/patologia
Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (MKKS protein, human); 0 (SMARCC1 protein, human); 0 (Transcription Factors); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006936


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[PMID]:28143435
[Au] Autor:Esposito G; Testa F; Zacchia M; Crispo AA; Di Iorio V; Capolongo G; Rinaldi L; D'Antonio M; Fioretti T; Iadicicco P; Rossi S; Franzè A; Marciano E; Capasso G; Simonelli F; Salvatore F
[Ad] Endereço:CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy.
[Ti] Título:Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.
[So] Source:BMC Med Genet;18(1):10, 2017 Feb 01.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. METHODS: We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. RESULTS: At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. CONCLUSION: BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.
[Mh] Termos MeSH primário: Síndrome de Bardet-Biedl/genética
Grupo com Ancestrais do Continente Europeu/genética
Olho/fisiopatologia
Rim/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Limiar Auditivo
Síndrome de Bardet-Biedl/patologia
Criança
DNA/química
DNA/isolamento & purificação
DNA/metabolismo
Análise Mutacional de DNA
Olho/diagnóstico por imagem
Feminino
Estudos de Associação Genética
Genótipo
Chaperoninas do Grupo II/genética
Seres Humanos
Itália
Masculino
Proteínas Associadas aos Microtúbulos/genética
Meia-Idade
Fenótipo
Polimorfismo Genético
Proteínas/genética
Tomografia de Coerência Óptica
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BBS10 protein, human); 0 (Bbs1 protein, human); 0 (Bbs2 protein, human); 0 (Microtubule-Associated Proteins); 0 (Proteins); 9007-49-2 (DNA); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0372-0


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[PMID]:26968886
[Au] Autor:Yamamura T; Morisada N; Nozu K; Minamikawa S; Ishimori S; Toyoshima D; Ninchoji T; Yasui M; Taniguchi-Ikeda M; Morioka I; Nakanishi K; Nishio H; Iijima K
[Ad] Endereço:Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
[Ti] Título:Rare renal ciliopathies in non-consanguineous families that were identified by targeted resequencing.
[So] Source:Clin Exp Nephrol;21(1):136-142, 2017 Feb.
[Is] ISSN:1437-7799
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) are a frequent cause of renal failure for children and adolescents. Although diagnosing these diseases clinically is difficult, a comprehensive genetic screening approach of targeted resequencing can uncover the genetic background in this complicated family of diseases. METHODS: We studied three Japanese female patients with renal insufficiency from non-consanguineous parents. A renal biopsy for clinical reasons was not performed. Therefore, we did not know the diagnosis of these patients from a clinical aspect. We performed comprehensive genetic analysis using the TruSight One Sequencing Panel next generation sequencing technique. RESULTS: We identified three different rare NPHP-RC variants in the following genes: SDCCAG8, MKKS, and WDR35. Patient 1 with SDCCAG8 homozygous deletions showed no ciliopathy-specific extrarenal manifestations, such as retinitis pigmentosa or polydactyly prior to genetic analysis. Patient 2 with a MKKS splice site homozygous mutation and a subsequent 39-amino acid deletion in the substrate-binding apical domain, had clinical symptoms of Bardet-Biedl syndrome. She and her deceased elder brother had severe renal insufficiency soon after birth. Patient 3 with a compound heterozygous WDR35 mutation had ocular coloboma and intellectual disability. CONCLUSIONS: Our results suggest that a comprehensive genetic screening system using target resequencing is useful and non-invasive for the diagnosis of patients with an unknown cause of pediatric end-stage renal disease.
[Mh] Termos MeSH primário: Autoantígenos/genética
Ciliopatias/genética
Análise Mutacional de DNA
Testes Genéticos/métodos
Chaperoninas do Grupo II/genética
Sequenciamento de Nucleotídeos em Larga Escala
Nefropatias/genética
Proteínas de Neoplasias/genética
Proteínas/genética
Deleção de Sequência
[Mh] Termos MeSH secundário: Adolescente
Adulto
Pré-Escolar
Ciliopatias/diagnóstico
Consanguinidade
Progressão da Doença
Feminino
Marcadores Genéticos
Predisposição Genética para Doença
Heterozigoto
Homozigoto
Seres Humanos
Nefropatias/diagnóstico
Falência Renal Crônica/diagnóstico
Falência Renal Crônica/genética
Imagem por Ressonância Magnética
Fenótipo
Valor Preditivo dos Testes
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (Genetic Markers); 0 (MKKS protein, human); 0 (Neoplasm Proteins); 0 (Proteins); 0 (SDCCAG8 protein, human); 0 (WDR35 protein, human); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160313
[St] Status:MEDLINE
[do] DOI:10.1007/s10157-016-1256-x


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[PMID]:27432832
[Au] Autor:Shah R; Large AT; Ursinus A; Lin B; Gowrinathan P; Martin J; Lund PA
[Ad] Endereço:School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
[Ti] Título:Replacement of GroEL in Escherichia coli by the Group II Chaperonin from the Archaeon Methanococcus maripaludis.
[So] Source:J Bacteriol;198(19):2692-700, 2016 Oct 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Chaperonins are required for correct folding of many proteins. They exist in two phylogenetic groups: group I, found in bacteria and eukaryotic organelles, and group II, found in archaea and eukaryotic cytoplasm. The two groups, while homologous, differ significantly in structure and mechanism. The evolution of group II chaperonins has been proposed to have been crucial in enabling the expansion of the proteome required for eukaryotic evolution. In an archaeal species that expresses both groups of chaperonins, client selection is determined by structural and biochemical properties rather than phylogenetic origin. It is thus predicted that group II chaperonins will be poor at replacing group I chaperonins. We have tested this hypothesis and report here that the group II chaperonin from Methanococcus maripaludis (Mm-cpn) can partially functionally replace GroEL, the group I chaperonin of Escherichia coli Furthermore, we identify and characterize two single point mutations in Mm-cpn that have an enhanced ability to replace GroEL function, including one that allows E. coli growth after deletion of the groEL gene. The biochemical properties of the wild-type and mutant Mm-cpn proteins are reported. These data show that the two groups are not as functionally diverse as has been thought and provide a novel platform for genetic dissection of group II chaperonins. IMPORTANCE: The two phylogenetic groups of the essential and ubiquitous chaperonins diverged approximately 3.7 billion years ago. They have similar structures, with two rings of multiple subunits, and their major role is to assist protein folding. However, they differ with regard to the details of their structure, their cofactor requirements, and their reaction cycles. Despite this, we show here that a group II chaperonin from a methanogenic archaeon can partially substitute for the essential group I chaperonin GroEL in E. coli and that we can easily isolate mutant forms of this chaperonin with further improved functionality. This is the first demonstration that these two groups, despite the long time since they diverged, still overlap significantly in their functional properties.
[Mh] Termos MeSH primário: Proteínas Arqueais/metabolismo
Chaperonina 60/metabolismo
Escherichia coli/metabolismo
Chaperoninas do Grupo II/metabolismo
Mathanococcus/genética
[Mh] Termos MeSH secundário: Proteínas Arqueais/genética
Chaperonina 60/genética
Deleção de Genes
Regulação da Expressão Gênica em Archaea
Chaperoninas do Grupo II/genética
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (Chaperonin 60); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160720
[St] Status:MEDLINE
[do] DOI:10.1128/JB.00317-16


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[PMID]:27245532
[Au] Autor:Fieggen K; Milligan C; Henderson B; Esterhuizen AI
[Ad] Endereço:Division of Human Genetics, Department of Medicine, University of Cape Town, South Africa. karen.fieggen@uct.ac.za.
[Ti] Título:Bardet Biedl syndrome in South Africa: A single founder mutation.
[So] Source:S Afr Med J;106(6 Suppl 1):S72-4, 2016 May 25.
[Is] ISSN:0256-9574
[Cp] País de publicação:South Africa
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA. METHOD: This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. RESULTS: A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.
[Mh] Termos MeSH primário: Síndrome de Bardet-Biedl/genética
Efeito Fundador
Testes Genéticos/métodos
Chaperoninas do Grupo II/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Grupo com Ancestrais do Continente Africano/genética
Síndrome de Bardet-Biedl/epidemiologia
Síndrome de Bardet-Biedl/fisiopatologia
Criança
Pré-Escolar
Estudos Transversais
Feminino
Heterozigoto
Homozigoto
Seres Humanos
Lactente
Masculino
Mutação
Fenótipo
Estudos Retrospectivos
África do Sul/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BBS10 protein, human); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160602
[St] Status:MEDLINE
[do] DOI:10.7196/SAMJ.2016.v106i6.11000


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[PMID]:27079363
[Au] Autor:Zako T; Sahlan M; Fujii S; Yamamoto YY; Tai PT; Sakai K; Maeda M; Yohda M
[Ad] Endereço:Bioengineering Laboratory, RIKEN Institute, Saitama, Japan.
[Ti] Título:Contribution of the C-Terminal Region of a Group II Chaperonin to its Interaction with Prefoldin and Substrate Transfer.
[So] Source:J Mol Biol;428(11):2405-17, 2016 Jun 05.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Prefoldin is a molecular chaperone that captures an unfolded protein substrate and transfers it to a group II chaperonin. Previous studies have shown that the interaction sites for prefoldin are located in the helical protrusions of group II chaperonins. However, it does not exclude the possibility of the existence of other interaction sites. In this study, we constructed C-terminal truncation mutants of a group II chaperonin and examined the effects of these mutations on the chaperone's function and interaction with prefoldin. Whereas the mutants with up to 6 aa truncation from the C-terminus retained more than 90% chaperone activities for protecting citrate synthase from thermal aggregation and refolding of green fluorescent protein and isopropylmalate dehydrogenase, the truncation mutants showed decreased affinities for prefoldin. Consequently, the truncation mutants showed reduced transfer efficiency of the denatured substrate protein from prefoldin and subsequent chaperonin-dependent refolding. The results clearly show that the C-terminal region of group II chaperonins contributes to their interactions with prefoldin, the transfer of the substrate protein from prefoldin and its refolding.
[Mh] Termos MeSH primário: Chaperoninas do Grupo II/metabolismo
Chaperonas Moleculares/metabolismo
[Mh] Termos MeSH secundário: Citrato (si)-Sintase/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Chaperoninas do Grupo II/genética
Chaperonas Moleculares/genética
Mutação/genética
Agregados Proteicos/genética
Ligação Proteica/genética
Desnaturação Proteica
Dobramento de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Molecular Chaperones); 0 (Protein Aggregates); 0 (prefoldin); 147336-22-9 (Green Fluorescent Proteins); EC 2.3.3.1 (Citrate (si)-Synthase); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160416
[St] Status:MEDLINE


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[PMID]:27021162
[Au] Autor:Hoersch D; Kortemme T
[Ad] Endereço:Department of Physics, Freie Universität Berlin, Berlin 14195, Germany; Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: daniel.hoersch@fu-berlin.de.
[Ti] Título:A Model for the Molecular Mechanism of an Engineered Light-Driven Protein Machine.
[So] Source:Structure;24(4):576-584, 2016 Apr 05.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Controllable protein-based machines and materials are of considerable interest for diverse biotechnological applications. We previously re-engineered an ATP-driven protein machine, a group II chaperonin, to function as a light-gated nanocage. Here we develop and test a model for the molecular mechanism of the re-engineered chaperonin, which undergoes a large-scale closed to open conformational change triggered by reversible photo-isomerization of a site-specifically attached azobenzene crosslinker. In silico experiments using all-atom simulations suggest that rigid body motions of protein subdomains couple the length changes of the crosslinker to rearrangements of the nucleotide-binding pocket, leading to cage opening. We tested this model by designing a mutant for which the orientation of the two protein subdomains forming the nucleotide-binding pocket is directly controlled by the crosslinker, and confirmed successful reversible photoswitching in vitro. The model probes the conformational cycle of group II chaperonins and offers a design principle for engineering other light-driven protein-based molecular machines.
[Mh] Termos MeSH primário: Compostos Azo/metabolismo
Chaperoninas do Grupo II/química
Chaperoninas do Grupo II/genética
[Mh] Termos MeSH secundário: Sítios de Ligação
Simulação por Computador
Reagentes para Ligações Cruzadas
Microscopia Crioeletrônica
Chaperoninas do Grupo II/metabolismo
Luz
Modelos Moleculares
Mutação
Ligação Proteica
Conformação Proteica
Engenharia de Proteínas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Azo Compounds); 0 (Cross-Linking Reagents); EC 3.6.1.- (Group II Chaperonins); F0U1H6UG5C (azobenzene)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170903
[Lr] Data última revisão:
170903
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160330
[St] Status:MEDLINE


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[PMID]:26900326
[Au] Autor:Hulleman JD; Nguyen A; Ramprasad VL; Murugan S; Gupta R; Mahindrakar A; Angara R; Sankurathri C; Mootha VV
[Ad] Endereço:Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX.
[Ti] Título:A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome.
[So] Source:Mol Vis;22:73-81, 2016.
[Is] ISSN:1090-0535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS. METHODS: The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT) imaging, and an extensive physical examination with abdominal ultrasonography to characterize the disease phenotype. Next-generation sequencing (NGS) using a panel targeting retinal degeneration genes was performed on genomic DNA samples from the siblings and parents. Upon identification of the causative mutation, functional characterization was accomplished by performing protein-protein interaction studies in human embryonic kidney (HEK-293T) and human adult retinal pigmented epithelium (ARPE-19) cells. RESULTS: The two siblings showed signs of RP and polydactyly. The patients did not have truncal obesity, renal anomalies, hydrometrocolpos, congenital heart disease, or overt cognitive defects. NGS identified a homozygous c.1184A>G mutation in the MKKS/BBS6 gene in both patients resulting in a p.H395R substitution in the MKKS/BBS6 protein. This mutant protein decreased the interaction of MKKS/BBS6 with BBS12 but did so to a different extent in the HEK-293T versus ARPE-19 cells. Nonetheless, the effect of the H395R variant on disrupting interactions with BBS12 was not as profound as other reported MKKS/BBS6 mutations associated with syndromic RP. CONCLUSIONS: We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only RP and polydactyly. Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings.
[Mh] Termos MeSH primário: Anormalidades Múltiplas/genética
Síndrome de Bardet-Biedl/genética
Chaperoninas do Grupo II/genética
Cardiopatias Congênitas/genética
Hidrocolpos/genética
Mutação de Sentido Incorreto
Polidactilia/genética
Retinite Pigmentosa/genética
Doenças Uterinas/genética
[Mh] Termos MeSH secundário: Adolescente
Western Blotting
Consanguinidade
Análise Mutacional de DNA
Feminino
Células HEK293
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Linhagem
Plasmídeos
Epitélio Pigmentado da Retina/citologia
Irmãos
Tomografia de Coerência Óptica
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (MKKS protein, human); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160223
[St] Status:MEDLINE


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[PMID]:26856373
[Au] Autor:Paul DM; Beuron F; Sessions RB; Brancaccio A; Bigotti MG
[Ad] Endereço:School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK.
[Ti] Título:Internal (His)6-tagging delivers a fully functional hetero-oligomeric class II chaperonin in high yield.
[So] Source:Sci Rep;6:20696, 2016 Feb 09.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Group II chaperonins are ATP-ases indispensable for the folding of many proteins that play a crucial role in Archaea and Eukarya. They display a conserved two-ringed assembly enclosing an internal chamber where newly translated or misfolded polypeptides can fold to their native structure. They are mainly hexadecamers, with each eight-membered ring composed of one or two (in Archaea) or eight (in Eukarya) different subunits. A major recurring problem within group II chaperonin research, especially with the hetero-oligomeric forms, is to establish an efficient recombinant system for the expression of large amounts of wild-type as well as mutated variants. Herein we show how we can produce, in E. coli cells, unprecedented amounts of correctly assembled and active αß-thermosome, the class II chaperonin from Thermoplasma acidophilum, by introducing a (His)6-tag within a loop in the α subunit of the complex. The specific location was identified via a rational approach and proved not to disturb the structure of the chaperonin, as demonstrated by size-exclusion chromatography, native gel electrophoresis and electron microscopy. Likewise, the tagged protein showed an ATP-ase activity and an ability to refold substrates identical to the wild type. This tagging strategy might be employed for the overexpression of other recombinant chaperonins.
[Mh] Termos MeSH primário: Proteínas Arqueais
Chaperoninas do Grupo II
Histidina
Proteínas Recombinantes de Fusão
Thermoplasma/genética
[Mh] Termos MeSH secundário: Proteínas Arqueais/biossíntese
Proteínas Arqueais/genética
Chaperoninas do Grupo II/biossíntese
Chaperoninas do Grupo II/genética
Histidina/biossíntese
Histidina/genética
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (Recombinant Fusion Proteins); 26062-48-6 (polyhistidine); 4QD397987E (Histidine); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160210
[St] Status:MEDLINE
[do] DOI:10.1038/srep20696


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[PMID]:26853941
[Au] Autor:Chaston JJ; Smits C; Aragão D; Wong AS; Ahsan B; Sandin S; Molugu SK; Molugu SK; Bernal RA; Stock D; Stewart AG
[Ad] Endereço:Molecular, Structural and Computational Biology Division, The Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.
[Ti] Título:Structural and Functional Insights into the Evolution and Stress Adaptation of Type II Chaperonins.
[So] Source:Structure;24(3):364-74, 2016 Mar 01.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chaperonins are essential biological complexes assisting protein folding in all kingdoms of life. Whereas homooligomeric bacterial GroEL binds hydrophobic substrates non-specifically, the heterooligomeric eukaryotic CCT binds specifically to distinct classes of substrates. Sulfolobales, which survive in a wide range of temperatures, have evolved three different chaperonin subunits (α, ß, γ) that form three distinct complexes tailored for different substrate classes at cold, normal, and elevated temperatures. The larger octadecameric ß complexes cater for substrates under heat stress, whereas smaller hexadecameric αß complexes prevail under normal conditions. The cold-shock complex contains all three subunits, consistent with greater substrate specificity. Structural analysis using crystallography and electron microscopy reveals the geometry of these complexes and shows a novel arrangement of the α and ß subunits in the hexadecamer enabling incorporation of the γ subunit.
[Mh] Termos MeSH primário: Proteínas Arqueais/química
Proteínas Arqueais/metabolismo
Chaperoninas do Grupo II/química
Chaperoninas do Grupo II/metabolismo
Sulfolobus solfataricus/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Evolução Molecular
Cinética
Microscopia Eletrônica
Modelos Moleculares
Filogenia
Multimerização Proteica
Estrutura Secundária de Proteína
Especificidade por Substrato
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Archaeal Proteins); EC 3.6.1.- (Group II Chaperonins)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160209
[St] Status:MEDLINE



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