The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2−/− are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2+/− mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.
RPGR-interacting protein 1 (RPGRIP1) is a key component of cone and rod photoreceptor cells, where it interacts with RPGR (retinitis pigmentosa GTPase regulator). Mutations in RPGRIP1lead to autosomal recessive congenital blindness [Leber congenital amaurosis (LCA)]. Most LCA-associated missense mutations in RPGRIP1 are located in a segment that encodes two C2 domains. Based on the C2 domain of novel protein kinase C (PKC ), we built a 3D-homology model for the C-terminal C2 domain of RPGRIP1. This model revealed a potential Ca 2؉ -binding site that was predicted to be disrupted by a missense mutation in RPGRIP1, which was previously identified in an LCA patient. Through yeast two-hybrid screening of a retinal cDNA library, we found this C2 domain to specifically bind to nephrocystin-4, encoded by NPHP4. Mutations in NPHP4 are associated with nephronophthisis and a combination of nephronophthisis and retinitis pigmentosa called Senior-Løken syndrome (SLSN). We show that RPGRIP1 and nephrocystin-4 interact strongly in vitro and in vivo, and that they colocalize in the retina, matching the panretinal localization pattern of specific RPGRIP1 isoforms. Their interaction is disrupted by either mutations in RPGRIP1, found in patients with LCA, or by mutations in NPHP4, found in patients with nephronophthisis or SLSN. Thus, we provide evidence for the involvement of this disrupted interaction in the retinal dystrophy of both SLSN and LCA patients.T he X-linked gene RPGR (retinitis pigmentosa GTPase regulator) is mutated in patients with retinitis pigmentosa type 3 (RP3) (1, 2), cone or cone-rod dystrophy (COD1) (3, 4), atrophic macular degeneration (5), and RP in combination with impaired hearing and sinorespiratory infections (6). All RP3-associated missense mutations in RPGR have been identified in the N-terminal RCC1-homologous domain, and they disrupt the interaction with the C-terminal domain of RPGR-interacting protein 1 (RPGRIP1) (7,8). Mutations in RPGRIP1 lead to Leber congenital amaurosis (LCA), a genetically heterogeneous recessive disorder that is regarded to be the earliest and most severe form of all retinal dystrophies (9, 10). LCA accounts for at least 5% of all retinal dystrophies and is one of the main causes for blindness in children (11). RPGR and RPGRIP1 isoforms have been found to colocalize at the connecting cilia as well as the outer segments of rod and cone photoreceptors (12, 13). Differential localization among species has also been reported (12,14), and different isoforms of RPGRIP1 have been described resulting from splicing variation (7,14,15). The distinct partitioning of a subset of RPGRIP1 isoforms between the nuclear and cytoplasmic compartments combined with the differential and limited proteolysis of RPGRIP1 among retinal neurons, and the impact of LCA-linked mutations in RPGRIP1 in these processes, support the involvement of nucleocytoplasmatic signaling processes mediated by RPGRIP1 and its interacting partners in the pathogenesis of LCA, RP3, and allied diseases (15, 16). The pres...
Purpose: Guided bone regeneration (GBR) utilizes a barrier membrane to allow osteogenic cells to populate a space by excluding epithelial and connective tissue cells.The purpose of this systematic review was to investigate the ratio of means (RoM) of vertical bone gained (Outcome) in vertical GBR procedures with healing complications (Intervention) and in vertical GBR procedures without healing complications (Comparison) in patients with vertically resorbed edentulous ridges that require dental implant placement (Population). A further aim was to investigate the incidence of complications after vertical GBR, and the influence of the timing of implant placement and regenerative devices on complications.Materials and Methods: MEDLINE (through PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched in duplicate up to, and including, November 2020 for randomized and controlled clinical trials and prospective and retrospective case series. Outcomes included patient-level and site-level RoM of vertical bone gain between healing complications and uneventful healing, and incidences of complications that occurred after vertical GBR. Random-effects and fixed-effects meta-analyses were performed where appropriate. This study was registered on PROSPERO (CRD42021226432).Results: A total of 31 publications were selected for the qualitative and quantitative analyses. The RoM of vertical bone gained was 0.65 [95% CI = 0.47, 0.91] and 0.62 [95% CI = 0.45, 0.85] when membrane exposure without suppuration and abscess formation without membrane exposure occurred respectively, in comparison to uneventful healing. The overall incidence proportion of healing complications occurring at the augmented site at a site-and patient-level was 11.0% [95% CI = 7.0, 15.6] and 10.8% [95% CI = 6.6, 15.7]. At a patient-level, there were no significant differences between a simultaneous or staged approach, or with the regenerative device used. The site-level incidence proportion of membrane exposure without suppuration, membrane exposure with suppuration, and with abscess formation without membrane exposure was 8.7% [95% CI = 4.2, 14.2], 0.7% [95% CI = 0.0, 2.9], and 0.5% [95% CI = 0.0, 1.7], respectively. The site-level weighted mean incidence proportion of neurologic complications occurring at the donor site was 0.8% [95% CI = 0.0, 5.3].
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