Structure of human RNA polymerase III

In eukaryotes, RNA Polymerase (Pol) III is specialized for the transcription of tRNAs and other short, untranslated RNAs. Pol III is a determinant of cellular growth and lifespan across eukaryotes. Upregulation of Pol III transcription is observed in cancer and causative Pol III mutations have been described in neurodevelopmental disorders and hypersensitivity to viral infection. Here, we report a cryo-EM reconstruction at 4.0 Å of human Pol III, allowing mapping and rationalization of reported genetic mutations. Mutations causing neurodevelopmental defects cluster in hotspots affecting Pol III stability and/or biogenesis, whereas mutations affecting viral sensing are located in proximity to DNA binding regions, suggesting an impairment of Pol III cytosolic viral DNA-sensing. Integrating x-ray crystallography and SAXS, we also describe the structure of the higher eukaryote specific RPC5 C-terminal extension. Surprisingly, experiments in living cells highlight a role for this module in the assembly and stability of human Pol III

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

APPLICATION OF MODIFIED NEI VFQ-25 AFTER RETINAL DETACHMENT TO VISION-RELATED QUALITY OF LIFE.

We examined the postoperative visual recovery and quality of life after retinal detachment (RD) surgery. In addition to a baseline clinical examination, patients filled out the National Eye Institute Visual Functioning Questionnaire at three time points: preoperatively and 1 and 3 months postoperatively (M1 and M3, respectively). We analyzed the composite score and short-form scores (socioemotional scale [SFSES] and visual functioning scale [SFVFS]). One hundred ninety-four patients were enrolled in this study; 47 (26 macula-ON RD and 21 macula-OFF RD) returned all three questionnaires. The best corrected visual acuity was Snellen equivalent 20/25, 20/25, and 20/20 at the preoperative, M1, and M3 assessment, respectively. At M3, we found a positive correlation between SFSES and best corrected visual acuity measures among macula-OFF patients (P < 0.001, R2 = 0.58). A significant correlation with the best corrected visual acuity among macula-ON patients was observed only at M3 with the SFVFS score (P < 0.001, R2 = 0.41). The quality of life differs between ON and OFF RD in regard to the composite score and especially SFSES and SFVFS. We found a transient decrease in the quality of life at M1 for macula-ON patients, whereas the quality of life improved throughout follow-up among macula-OFF patients. These data may help improve the management of patients' expectations after RD surgery

EVOLUTION AND PATTERNS OF CHOROIDAL THICKNESS CHANGES IN RHEGMATOGENOUS RETINAL DETACHMENT.

To evaluate the changes in choroidal thickness (CT) before and after a successful pars plana vitrectomy for rhegmatogenous retinal detachment (RD), and to compare the evolution of CT with respect to the extent of RD. Fifty-four patients were divided into three groups: peripheral macula-on RD (>3 mm from the fovea; 14 eyes); paracentral macula-on RD (fovea-sparing; ≤3 mm from the fovea; 14 eyes); and macula-off RD (involving the fovea; 26 eyes). Choroidal thickness was measured at 1 month (M1) and 3 months (M3) postoperatively, preoperatively in macula-on RDs, with enhanced depth imaging optical coherence tomography, from the nasal side (+2.5 mm) to the temporal side (-2.5 mm) of the fovea. In peripheral macula-on RD, the intereye difference in CTs showed thickening throughout follow-up (subfoveally: preoperatively = 19.6% ± 43.9%, M1 = 22.9% ± 27.5%, M3 = 18.2% ± 35.6%). In paracentral macula-on RD, the intereye difference in CTs showed a thinning throughout follow-up (subfoveally: preoperatively = -7.8% ± 21.9%, M1 =-5.5% ± 26.1%, M3 = -9.3% ± 19.4%), as well as in the macula-off RD (subfoveally: M1 = -14.1% ± 18.7%, M3 = -9.9% ± 15%). The extent of RD was related to the evolution of the CT before and after surgery. Further studies are necessary to clarify the relationship between the changes in CT and the effects of circulatory alterations, vitrectomy, and RD

Primary rhegmatogenous retinal detachment: risk factors for macular involvement.

Rhegmatogenous retinal detachment (RD) has diagnostically been divided into macula-OFF or macula-ON. The aim of this study was to describe the demographics and primary outcome of patients with RD following surgery with respect to the macular status, and to determine risk factors for macular involvement. This prospective, observational, mono-centric cohort study was conducted at the Jules-Gonin Eye Hospital, from February 2015 until March 2017. The study included 194 eligible patients with primary RD. All patients underwent surgical treatment after baseline clinical examination. The dataset was analyzed using descriptive and analytic statistics. A total of 52.6% (102/194) of patients presented with macula-OFF RD. Mean age was 63.9 ± 12.0 vs. 59.7 ± 11.2 years in the OFF and ON group, respectively. There were 129 men (66.5%) and 65 (33.5%) women, and there were significantly more right eyes affected [right vs. left eyes 123 (63.4%) vs. 71 (36.6%), p = 0.000]. Significantly more myopes (<-3D) presented with a macula-ON RD (p = 0.04). There were more phakic patients in the cohort (55.7%), and phakic eyes were more likely to present with macula-ON RD (p = 0.01). Multivariate modeling showed that pseudophakic lens status and eyes with axial length less than 25 mm (p = 0.06) are independent predictive factors for macula-OFF RD (p = 0.02), whereas sex and laterality were not risk factors for macular involvement. Pseudophakic lens status and axial length < 25 mm are independent predictive factors for macula-OFF RD. While pseudophakic lens status is a recognized risk factor for RD, shorter axial length has not been previously identified as a risk factor for the macula-OFF RD