| [PMID]: | 29338044 |
| [Au] Autor: | Andley UP; Tycksen E; McGlasson-Naumann BN; Hamilton PD |
| [Ad] Endereço: | Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America. |
| [Ti] Título: | Probing the changes in gene expression due to α-crystallin mutations in mouse models of hereditary human cataract. |
| [So] Source: | PLoS One;13(1):e0190817, 2018. |
| [Is] ISSN: | 1932-6203 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The mammalian eye lens expresses a high concentration of crystallins (α, ß and γ-crystallins) to maintain the refractive index essential for lens transparency. Crystallins are long-lived proteins that do not turnover throughout life. The structural destabilization of crystallins by UV exposure, glycation, oxidative stress and mutations in crystallin genes leads to protein aggregation and development of cataracts. Several destabilizing mutations in crystallin genes are linked with human autosomal dominant hereditary cataracts. To investigate the mechanism by which the α-crystallin mutations Cryaa-R49C and Cryab-R120G lead to cataract formation, we determined whether these mutations cause an altered expression of specific transcripts in the lens at an early postnatal age by RNA-seq analysis. Using knock-in mouse models previously generated in our laboratory, in the present work, we identified genes that exhibited altered abundance in the mutant lenses, including decreased transcripts for Clic5, an intracellular water channel in Cryaa-R49C heterozygous mutant lenses, and increased transcripts for Eno1b in Cryab-R120G heterozygous mutant lenses. In addition, RNA-seq analysis revealed increased histones H2B, H2A, and H4 gene expression in Cryaa-R49C mutant lenses, suggesting that the αA-crystallin mutation regulates histone expression via a transcriptional mechanism. Additionally, these studies confirmed the increased expression of histones H2B, H2A, and H4 by proteomic analysis of Cryaa-R49C knock-in and Cryaa;Cryab gene knockout lenses reported previously. Taken together, these findings offer additional insight into the early transcriptional changes caused by Cryaa and Cryab mutations associated with autosomal dominant human cataracts, and indicate that the transcript levels of certain genes are affected by the expression of mutant α-crystallin in vivo. |
| [Mh] Termos MeSH primário: |
Catarata/genética
Mutação
Cadeia A de alfa-Cristalina/genética
Cadeia B de alfa-Cristalina/genética
|
| [Mh] Termos MeSH secundário: |
Animais
Carboxipeptidases/genética
Carboxipeptidases/metabolismo
Catarata/metabolismo
Canais de Cloreto/genética
Canais de Cloreto/metabolismo
Modelos Animais de Doenças
Expressão Gênica
Técnicas de Introdução de Genes
Histonas/genética
Histonas/metabolismo
Seres Humanos
Cristalino/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Mutantes
Camundongos Transgênicos
Proteínas/genética
Proteínas/metabolismo
Proteômica
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Cadeia A de alfa-Cristalina/metabolismo
Cadeia B de alfa-Cristalina/metabolismo
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL |
[Nm] Nome de substância:
| 0 (Aebp1 protein, mouse); 0 (CLIC5 protein, mouse); 0 (Chloride Channels); 0 (Cryab protein, mouse); 0 (Histones); 0 (Proteins); 0 (Repressor Proteins); 0 (alpha-Crystallin A Chain); 0 (alpha-Crystallin B Chain); 0 (vig1 protein, mouse); EC 3.4.- (Carboxypeptidases) |
| [Em] Mês de entrada: | 1802 |
| [Cu] Atualização por classe: | 180213 |
[Lr] Data última revisão:
| 180213 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 180117 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1371/journal.pone.0190817 |
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