Journal
SCIENCE
Volume 332, Issue 6026, Pages 238-240Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1200587
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Funding
- Ohio Supercomputing Center [PAS0425-2]
- Cleveland Foundation [L2009-0078]
- NIH [GM093074, GM079527]
- National Cancer Institute [P30 CA16058]
- OSU Comprehensive Cancer Center
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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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