Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I
H He, S Liyanarachchi, K Akagi, R Nagy, J Li… - science, 2011 - science.org
H He, S Liyanarachchi, K Akagi, R Nagy, J Li, RC Dietrich, W Li, N Sebastian, B Wen, B Xin…
science, 2011•science.orgSmall 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 …
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 …
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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