Mutations in LRPAP1 are associated with severe myopia in humans

Am J Hum Genet. 2013 Aug 8;93(2):313-20. doi: 10.1016/j.ajhg.2013.06.002. Epub 2013 Jul 3.


Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-β activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-β in cells from affected individuals, the latter being consistent with available data on the role of TGF-β in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-β signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Cathepsin H / genetics*
  • Cathepsin H / metabolism
  • Child
  • Child, Preschool
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease
  • Homozygote
  • Humans
  • Infant
  • LDL-Receptor Related Protein-Associated Protein / genetics*
  • LDL-Receptor Related Protein-Associated Protein / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Male
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / metabolism
  • Marfan Syndrome / pathology
  • Mice
  • Mutation*
  • Myopia / genetics*
  • Myopia / metabolism
  • Myopia / pathology
  • Pedigree
  • Phenotype
  • Sclera / metabolism
  • Sclera / pathology
  • Severity of Illness Index
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism


  • LDL-Receptor Related Protein-Associated Protein
  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Transforming Growth Factor beta
  • CTSH protein, human
  • Cathepsin H