Mutations in the RNA Granule Component TDRD7 Cause Cataract and Glaucoma

Abstract

The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis. TDRD7 is a Tudor domain RNA binding protein that is expressed in lens fiber cells in distinct TDRD7-RGs that interact with STAU1-ribonucleoproteins (RNPs). TDRD7 coimmunoprecipitates with specific lens messenger RNAs (mRNAs) and is required for the posttranscriptional control of mRNAs that are critical to normal lens development and to RG function. These findings demonstrate a role for RGs in vertebrate organogenesis.

Tudor domain containing 7 ( Tdrd7 ) is essential for dynamic ribonucleoprotein (RNP) remodeling of chromatoid bodies during spermatogenesis

“…Thus, Tdrd7 and Tdrd6 constitute a spermiogenic class of tudor family genes, which function in a sequential and nonredundant manner. A recent study unveiled that Tdrd7 has an additional somatic function in the eye and controls the development of cataracts as well as glaucoma (19), which we also observed in our aged Tdrd7 −/− mice ( Fig. S3 AA and AB).…”

“…Unlike other Tdrd genes, Tdrd7 mutation causes other somatic phenotypes, cataracts and glaucoma, which become severe with age. These ocular disorders were reported in one N-ethyl-N-nitrosourea point mutant mouse line and in two human cases (a patient and family) (19), and we also confirmed cataracts in our Tdrd7 −/− gene-targeted null mice (Fig. S3 AA and AB).…”

“…S1D). The role of Tdrd7 in eye development was recently described (19). In this study, we made a gene-targeted null mutation of Tdrd7 (Fig.…”

The LOTUS domain is a conserved DEAD-box RNA helicase regulator essential for the recruitment of Vasa to the germ plasm and nuage

“…In mice, MARF1 is oocyte-specific and required for meiotic progression, and MARF1 mutant mouse females are sterile (Su et al 2012). In contrast, mammalian TDRD5 and TDRD7 have important roles during spermatogenesis, and TDRD5-or TDRD7-deficient males are sterile (Lachke et al 2011;Tanaka et al 2011;Yabuta et al 2011). In Drosophila, the TDRD5 and TDRD7 orthologs Tejas and Tapas are jointly required for localization of Vasa to the nuage and play a role in piRNA-mediated retrotransposon silencing (Patil and Kai 2010;Patil et al 2014).…”

90 Focus on a clear message: conserved RNA binding proteins function in mRNA control in eye lens development and their deficiency causes cataract

“…These data represents the first example of a novel RNA binding protein-mediated mechanism for controlling cell cycle regulators in mammalian eye development and moreover, has broader significance given that the human genome encodes several hundred RNA binding proteins but to date less than twenty have been directly associated with mammalian developmental defects or disease. Finally, the findings on Celf1, taken in context of our recent discovery on the conserved function of a Tudor protein Tdrd7 in human, mouse and chicken eye development (Lachke et al, 2011) suggest that conserved post-transcriptional regulatory circuitries have evolved to control eye development in vertebrates.…”