Biochemical defects in minor spliceosome function in the developmental disorder MOPD I.
Biochemical defects in minor spliceosome function in the developmental disorder MOPD I.
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DOI：
10.1261/rna.045187.114
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Padgett RA
中科院分区：
文献类型：
--
作者：
Jafarifar F;Dietrich RC;Hiznay JM;Padgett RA
This paper uses a variety of in vivo and in vitro assays to address the functional phenotypes of mutations in U4atac that cause the developmental disorder, MOPD I/TALS. Four such mutations inhibit the binding of essential proteins of the U4atac/U6atac di-snRNA and, in so doing, inhibit tri-snRNP assembly. Accordingly, inefficient splicing of U12-dependent introns because of tri-snRNP deficiency is the mechanistic basis for MOPD I disease. Biallelic mutations of the human RNU4ATAC gene, which codes for the minor spliceosomal U4atac snRNA, cause the developmental disorder, MOPD I/TALS. To date, nine separate mutations in RNU4ATAC have been identified in MOPD I patients. Evidence suggests that all of these mutations lead to abrogation of U4atac snRNA function and impaired minor intron splicing. However, the molecular basis of these effects is unknown. Here, we use a variety of in vitro and in vivo assays to address this question. We find that only one mutation, 124G>A, leads to significantly reduced expression of U4atac snRNA, whereas four mutations, 30G>A, 50G>A, 50G>C and 51G>A, show impaired binding of essential protein components of the U4atac/U6atac di-snRNP in vitro and in vivo. Analysis of MOPD I patient fibroblasts and iPS cells homozygous for the most common mutation, 51G>A, shows reduced levels of the U4atac/U6atac.U5 tri-snRNP complex as determined by glycerol gradient sedimentation and immunoprecipitation. In this report, we establish a mechanistic basis for MOPD I disease and show that the inefficient splicing of genes containing U12-dependent introns in patient cells is due to defects in minor tri-snRNP formation, and the MOPD I-associated RNU4ATAC mutations can affect multiple facets of minor snRNA function.
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