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.

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

“…It has been observed that some variants might be more penetrant or have a larger effect because familial aggregation of disease is observed. 10,11 While locus heterogeneity makes it difficult to identify factors unambiguously influencing the KTCN phenotype, the replication for any particular gene is expected to be rare.…”

The pathogenesis of keratoconus

“…47 Concordance is also high among monozygotic twins and a greater similarity of phenotype is observed in monozygotic twin pairs implying that genetic factors are likely to have a key role in the disease phenotype. 48 KC has been associated with a wide range of systemic and ocular conditions, for example Leber congenital amaurosis, 49 anterior polar cataract, 50 Brittle cornea syndrome, 51,52 and with a 10-300-fold higher prevalence in individuals with Down syndrome. 53,54 Interestingly, individuals with connective tissue disorders such as Ehlers Danlos syndrome have a higher prevalence of KC.…”

“…81 Of particular relevance, linkage analysis in combination with nextgeneration sequencing identified a heterozygous mutation in mir-184 in two families with dominant congenital cataract associated with a corneal phenotype that in some cases was consistent with KC. 50,82,83 To establish whether mutations in mir-184 were associated with KC, mir-184 was subsequently screened in a cohort of 780 KC patients. 84 Rare variants were identified in two (0.25%) patients, but the variants did not fully segregate with disease, suggesting that mir-184 variants are not a common cause of isolated KC.…”

The Epidemiology and Etiology of Keratoconus

“…Genome-wide linkage analysis of affected pedigrees has shown evidence of disease susceptibility genes mapping to several putative chromosomal loci. [48][49][50][51] …”