Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • sirtuin 1 Although the disease specific phenotype

    2018-10-24

    Although the disease specific phenotype identified in this study will be invaluable for demonstrating the efficacy of gene based therapeutics, two major questions remain: 1) why do some patients with TRNT1 variants develop the severe syndromic disease SIFD while others (i.e. the three presented in this study) have a photoreceptor cell selective phenotype; and, 2) how do hypomorphic mutations in TRNT1 alter cellular autophagy. TRNT1 is a tRNA nucleotidyltransferase that is responsible for adding the nucleotides CCA to the 3′ end of tRNA precursor molecules, a process that is absolutely required for the binding and transfer of sirtuin 1 during protein synthesis (Nagaike et al., 2001). In humans, TRNT1 is the only CCA adding enzyme that has been identified and it functions in nuclear, cytoplasmic and mitochondrial compartments (Nagaike et al., 2001; Reichert et al., 2001). It is somewhat surprising that mutations in this ubiquitously expressed gene, which when absent is incompatible with life, could cause a photoreceptor cell selective disease. Interestingly, it is not uncommon for mild variants in genes that are required for protein synthesis to induce a photoreceptor cell selective phenotype. For instance, mutations in several genes required for normal mRNA splicing (SNRNP200, RP9, PRPF3, PRPF8, and PRPF31), have been shown to cause non-syndromic RP (Deery et al., 2002; Inglehearn et al., 1993; Maubaret et al., 2011; Zhao et al., 2009). One possible explanation for this phenomenon is that cell types outside the retina express alternatively spliced isoforms or have homologous enzymes that are capable of compensating for mutation induced loss of function. In the case of TRNT1, an alternative splice variant, 60bp shorter than wild-type, has been identified (Lizano et al., 2007).This truncated version produces a functional protein with the ability to add one or both of the C residues, but unlike the full-length enzyme, lacks the ability to add the terminal A (Lizano et al., 2007). Interestingly, this variant is expressed in photoreceptor cells and, like the canonical isoform, includes the residues affected by RP mutations in the two families we previously described (DeLuca et al., 2016) (Supplemental Fig. 2). An alternative explanation relates to the unique structure and protein synthesis demands of the post-mitotic photoreceptor cell. As indicated above, retinal photoreceptors have an elaborate structure with highly organized outer segments that contain all of the components required for visual transduction. In rod photoreceptors, which comprise 90% of the photoreceptors of the human retina, the outer segments are constantly recycled at a rate of approximately 10% of their total volume per day (Kevany and Palczewski, 2010). Minor perturbations in protein synthesis that could be readily tolerated by cells with lower protein synthesis rates or cells that can still renew themselves from a pool of mitotically active progenitors, may disturb the precise stoichiometry of proteins required for normal outer segment formation and maintenance. As autophagy can act as a general defense mechanism to reduce cell stress, the elevated autophagy detected in this study may reflect the cells\' response to the stress created by a defect in protein synthesis. However, it is also possible that there is a yet unidentified direct link between TRNT1 and autophagy. As observed in patients with Alzheimer and Huntington Disease, TRNT1 mutations may directly reduce the production of proteins such as beclin-1 that are essential for the autophagic machinery. For instance, decreased levels of LAMP1 in 90-day patient-specific retinal organoids could either result from overactive autophagy, or decreased LAMP1 synthesis. In support of this hypothesis, Liwak-Muir and colleagues recently demonstrated that fibroblasts obtained from patients diagnosed with TRNT1-associated SIFD had reduced respiration rates due to a decrease in abundance of select proteins associated with the OXPHOS complexes (Liwak-Muir et al., 2016).