Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils

Abstract

Latent TGF-β-binding protein-2 (LTBP-2) is an extracellular matrix protein associated with microfibrils, but its function in vivo has not been well understood. Homozygous mutations in LTBP2 have been found in humans with genetic eye diseases such as congenital glaucoma and lens dislocation, but pathogenic mechanism has been unknown. In this study, we explore the in vivo function of LTBP-2 by generating Ltbp2^–/– mice. Ltbp2^–/– mice developed lens luxation caused by compromised ciliary zonule formation, suggesting that LTBP-2 is an essential component for the development of bundled ciliary zonule. Addition of recombinant LTBP-2 in the organ culture of eyes from Ltbp2^–/– mice restored ciliary zonule formation. The transfection study of human LTBP2 mutant cDNAs suggests that LTBP2 mutations cause structural alterations in the proteins, leading to secretion failure, and/or loss of binding with fibrillin-1. These data suggest an essential function of LTBP-2 in ciliary zonule microfibril development that could explain the pathological mechanism of human patients with LTBP2 mutations.