Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I

Science. 2011 Apr 8;332(6026):238-40. doi: 10.1126/science.1200587.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromosomes, Human, Pair 2 / genetics
  • Dwarfism / genetics
  • Dwarfism / metabolism
  • Female
  • Fetal Growth Retardation / genetics
  • Fetal Growth Retardation / metabolism
  • Humans
  • Introns
  • Inverted Repeat Sequences
  • Male
  • Microcephaly / genetics
  • Microcephaly / metabolism
  • Mutation*
  • Nucleic Acid Conformation
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / metabolism
  • Pedigree
  • RNA Splicing*
  • RNA, Small Nuclear / chemistry
  • RNA, Small Nuclear / genetics*
  • RNA, Small Nuclear / metabolism
  • Spliceosomes / genetics*
  • Spliceosomes / metabolism

Substances

  • RNA, Small Nuclear
  • U12 small nuclear RNA
  • U2 small nuclear RNA
  • U4 small nuclear RNA

Supplementary concepts

  • Microcephalic osteodysplastic primordial dwarfism, type 1