Mutation altering the miR-184 seed region causes familial keratoconus with cataract

Am J Hum Genet. 2011 Nov 11;89(5):628-33. doi: 10.1016/j.ajhg.2011.09.014. Epub 2011 Oct 11.


MicroRNAs (miRNAs) bind to complementary sequences within the 3' untranslated region (UTR) of mRNAs from hundreds of target genes, leading either to mRNA degradation or suppression of translation. We found that a mutation in the seed region of miR-184 (MIR184) is responsible for familial severe keratoconus combined with early-onset anterior polar cataract by deep sequencing of a linkage region known to contain the mutation. The mutant form fails to compete with miR-205 (MIR205) for overlapping target sites on the 3' UTRs of INPPL1 and ITGB4. Although these target genes and miR-205 are expressed widely, the phenotype is restricted to the cornea and lens because of the very high expression of miR-184 in these tissues. Our finding highlights the tissue specificity of a gene network regulated by a miRNA. Awareness of the important function of miRNAs could aid identification of susceptibility genes and new therapeutic targets for treatment of both rare and common diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Case-Control Studies
  • Cataract / congenital*
  • Cataract / genetics
  • Cornea / metabolism
  • HeLa Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Integrin beta4 / genetics
  • Keratoconus / genetics*
  • Lens, Crystalline / metabolism
  • MicroRNAs / genetics*
  • Mutation*
  • Northern Ireland
  • Organ Specificity / genetics*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / genetics
  • Polymorphism, Genetic
  • Sequence Analysis, RNA
  • Sequence Homology, Nucleic Acid


  • 3' Untranslated Regions
  • ITGB4 protein, human
  • Integrin beta4
  • MIRN184 microRNA, human
  • MIRN205 microRNA, human
  • MicroRNAs
  • Phosphoric Monoester Hydrolases
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Supplementary concepts

  • Cataract anterior polar dominant