title: Mutation altering the miR-184 seed region causes familial keratoconus with cataract.
abstract: 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.
authors: Centre for Public Health, The Queen's University of Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BN, Northern Ireland, UK. a.hughes@qub.ac.uk
authors: Anne E
authors: AE
authors: Hughes
authors: Declan T
authors: DT
authors: Bradley
authors: Malcolm
authors: M
authors: Campbell
authors: Judith
authors: J
authors: Lechner
authors: Durga P
authors: DP
authors: Dash
authors: David A
authors: DA
authors: Simpson
authors: Colin E
authors: CE
authors: Willoughby
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D016022:Case-Control Studies; D002386:Cataract / Q000151:congenital* / Q000235:genetics; D003315:Cornea / Q000378:metabolism; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics; D007640:Keratoconus / Q000235:genetics*; D007908:Lens, Crystalline / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D009660:Northern Ireland; D009928:Organ Specificity / Q000235:genetics*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011110:Polymorphism, Genetic; D017423:Sequence Analysis, RNA; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; D039663:Integrin beta4; D035683:MicroRNAs; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; C059834:ITGB4 protein, human; C534424:MIRN184 microRNA, human; C534425:MIR205, human; C098706:INPPL1 protein, human