PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa

Hum Mol Genet. 2011 Jun 1;20(11):2116-30. doi: 10.1093/hmg/ddr094. Epub 2011 Mar 5.


Proteins PRPF31, PRPF3 and PRPF8 (RP-PRPFs) are ubiquitously expressed components of the spliceosome, a macromolecular complex that processes nearly all pre-mRNAs. Although these spliceosomal proteins are conserved in eukaryotes and are essential for survival, heterozygous mutations in human RP-PRPF genes lead to retinitis pigmentosa, a hereditary disease restricted to the eye. Using cells from patients with 10 different mutations, we show that all clinically relevant RP-PRPF defects affect the stoichiometry of spliceosomal small nuclear RNAs (snRNAs), the protein composition of tri-small nuclear ribonucleoproteins and the kinetics of spliceosome assembly. These mutations cause inefficient splicing in vitro and affect constitutive splicing ex-vivo by impairing the removal of at least 9% of endogenously expressed introns. Alternative splicing choices are also affected when RP-PRPF defects are present. Furthermore, we show that the steady-state levels of snRNAs and processed pre-mRNAs are highest in the retina, indicating a particularly elevated splicing activity. Our results suggest a role for PRPFs defects in the etiology of PRPF-linked retinitis pigmentosa, which appears to be a truly systemic splicing disease. Although these mutations cause widespread and important splicing defects, they are likely tolerated by the majority of human tissues but are critical for retinal cell survival.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Female
  • Genes, Dominant
  • Heterozygote
  • Humans
  • Introns
  • Male
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • RNA Precursors / genetics*
  • RNA Splicing / genetics*
  • RNA, Small Nuclear / genetics*
  • RNA-Binding Proteins
  • Retina / metabolism
  • Retinitis Pigmentosa / genetics*
  • Ribonucleoprotein, U4-U6 Small Nuclear / genetics
  • Ribonucleoprotein, U4-U6 Small Nuclear / metabolism
  • Ribonucleoproteins, Small Nuclear / metabolism
  • Spliceosomes / metabolism
  • Spliceosomes / pathology*


  • Carrier Proteins
  • Eye Proteins
  • Nuclear Proteins
  • PRPF3 protein, human
  • PRPF31 protein, human
  • PRPF8 protein, human
  • RNA Precursors
  • RNA, Small Nuclear
  • RNA-Binding Proteins
  • Ribonucleoprotein, U4-U6 Small Nuclear
  • Ribonucleoproteins, Small Nuclear