CRISPR/Cas9 Editing of the Mouse Thra Gene Produces Models with Variable Resistance to Thyroid Hormone

被引：19

作者：

Markossian, Suzy ^{[1
]}

Guyot, Romain ^{[1
]}

Richard, Sabine ^{[1
]}

Teixeira, Marie ^{[2
]}

Aguilera, Nadine ^{[2
]}

Bouchet, Mathilde ^{[1
]}

Plateroti, Michelina ^{[3
]}

Guan, Wenyue ^{[1
]}

Gauthier, Karine ^{[1
]}

Aubert, Denise ^{[1
]}

Flamant, Frederic ^{[1
]}

机构：

[1] Univ Lyon, Inst Genom Fonct Lyon, INRA, CNRS,UMR 5242,USC 1370, Lyon, France

[2] Ecole Normale Super Lyon, Plateau Biol Expt Souris SFR Biosci, Lyon, France

[3] Ctr Rech Cancerol Lyon, Lyon, France

来源：

THYROID | 2018年 / 28卷 / 01期

关键词：

nuclear receptor; mouse model; CRISPR; Cas9; DOMINANT-NEGATIVE MUTATION; TR-ALPHA; CLINICAL PHENOTYPE; OFF-TARGET; RECEPTOR; MUTANT; MICE; THYROID-HORMONE-RECEPTOR-ALPHA-1; CONSEQUENCES; IMPAIRMENT;

D O I：

10.1089/thy.2017.0389

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background:Resistance to thyroid hormone due to THRA mutations (RTH) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TR1, one of the two nuclear receptors for thyroid hormone. Methods: The aim of this study was to understand the relationship between specific THRA mutations and phenotype. CRISPR/Cas9 genome editing was used to generate five new mouse models of RTH, with frameshift or missense mutations. Results: Like human patients, mutant mice displayed a hypothyroid-like phenotype, with altered development. Phenotype severity varied between the different mouse models, mainly depending on the ability of the mutant receptor to interact with transcription corepressor in the presence of thyroid hormone. Conclusion: The present mutant mice represent highly relevant models for the human genetic disease which will be useful for future investigations.

引用

页码：139 / 150

页数：12

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