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.

Abstract-Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca 2ϩ release events (Ca 2ϩ -sparks), trigger the activation of large-conductance Ca 2ϩ -activated K ϩ (BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca 2ϩ ] i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca 2ϩ -sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BK␣ subunit was unchanged. The Ca 2ϩ -sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BK␤1 subunit confers Ca 2ϩ -sensitivity to BK channel complexes and both transcript and protein levels for BK␤1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BK␤1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension. (Circ Res. 2007;100:703-711.)

Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

This is the first report of a family with autosomal dominant inheritance of keratoconus in association with cataract. The causative gene maps to the long arm of chromosome 15 but has not yet been identified.

Our data combined with the previously reported mutational spectrum of ZEB1 support a genotypephenotype correlation: missense substitutions in the ZEB1 protein are associated with FECD6 and keratoconus, whereas protein truncating ZEB1 mutations result in PPCD3. The dysregulation of α-type IV collagens represents a common link between ZEB1 mutation and the clinical phenotypes (PPCD3, FECD, and keratoconus).