Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I |
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Authors: | He Huiling Liyanarachchi Sandya Akagi Keiko Nagy Rebecca Li Jingfeng Dietrich Rosemary C Li Wei Sebastian Nikhil Wen Bernard Xin Baozhong Singh Jarnail Yan Pearlly Alder Hansjuerg Haan Eric Wieczorek Dagmar Albrecht Beate Puffenberger Erik Wang Heng Westman Judith A Padgett Richard A Symer David E de la Chapelle Albert |
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Affiliation: | Human Cancer Genetics Program, Ohio State University, Columbus, OH 43210, USA. |
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Abstract: | Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development. |
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