scholarly journals CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

2021 ◽  
Vol 22 (23) ◽  
pp. 12642
Author(s):  
Kévin Mairot ◽  
Vasily Smirnov ◽  
Béatrice Bocquet ◽  
Gilles Labesse ◽  
Carl Arndt ◽  
...  

Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.

2019 ◽  
Vol 98 (4) ◽  
Author(s):  
Andreas Bringmann ◽  
Tobias Duncker ◽  
Claudia Jochmann ◽  
Thomas Barth ◽  
Gernot I. W. Duncker ◽  
...  

1998 ◽  
Vol 15 (2) ◽  
pp. 211-218 ◽  
Author(s):  
ERIC M. WEXLER ◽  
OKSANA BERKOVICH ◽  
SCOTT NAWY

We have examined the role of neurotrophins in promoting survival of mammalian rod bipolar cells (RBC) in culture. Retinas taken from 8- to 10-day-old Long-Evans rats were dissociated and cultured in media supplemented with either nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), or basic fibroblast growth factor (FGF-2). Survival was measured by the number of cells that were immunoreactive for α-, β-, γ-PKC, a bipolar cell-specific marker. Compared to untreated cultures, CNTF had no effect on RBC survival, while NGF and NT-3 increased survival only slightly. BDNF, however, increased survival by approximately 300%. Similar results were obtained with FGF-2. Both nerve growth factor (NGF) and an antibody (anti-REX) which interferes with binding to the 75-kD low-affinity neurotrophin receptor (p75NTR) eliminated BDNF-promoted survival, but had no effect on FGF-2-mediated survival. Interestingly, p75NTR was expressed by retinal glia (Müller cells), but not by the bipolar cells themselves, providing for the possibility that BDNF might induce Müller cells to produce a secondary factor, perhaps FGF-2, which directly rescues RBCs. In support of this hypothesis, an antibody that neutralizes FGF-2 attenuated the trophic effects of BDNF, and dramatically reduced survival in cultures with no added growth factors, indicating that there may be an endogenous source of FGF-2 that promotes survival of RBCs in culture. We suggest that BDNF increases production or release of FGF-2 by binding to p75NTR on Müller cells.


Neuroscience ◽  
1993 ◽  
Vol 55 (1) ◽  
pp. 291-301 ◽  
Author(s):  
S. Tout ◽  
T. Chan-Ling ◽  
H. Holländer ◽  
J. Stone

2011 ◽  
Vol 52 (13) ◽  
pp. 9527 ◽  
Author(s):  
Robert J. Walker ◽  
Nancy M. Anderson ◽  
Youde Jiang ◽  
Suleiman Bahouth ◽  
Jena J. Steinle

Glia ◽  
2011 ◽  
Vol 59 (7) ◽  
pp. 1107-1117 ◽  
Author(s):  
Eun-Jin Lee ◽  
Yerina Ji ◽  
Colleen L. Zhu ◽  
Norberto M. Grzywacz

2019 ◽  
Vol 104 (4) ◽  
pp. 466-472 ◽  
Author(s):  
Andrea Govetto ◽  
Jean-Pierre Hubschman ◽  
David Sarraf ◽  
Marta S Figueroa ◽  
Ferdinando Bottoni ◽  
...  

BackgroundTo explore the role of foveal and parafoveal Müller cells in the morphology and pathophysiology of tractional macular disorders with a mathematical model of mechanical force transmission.MethodsIn this retrospective observational study, spectral-domain optical coherence tomography images of tractional lamellar macular holes and patients with myopic foveoschisis were reviewed and analysed with a mathematical model of force transmission. Parafoveal z-shaped Müller cells were modelled as a structure composed of three rigid rods, named R1, R2 and R3. The angle formed between the rods was referred to as θ . R1, R2 and R3 lengths as well as the variation of the angle θ were measured and correlated with best corrected visual acuity (BCVA).ResultsIn tractional lamellar macular holes, there was a significant reduction of the angle θ towards the foveal centre (p<0.001). By contrast, there were no significant differences in θ in myopic foveoschisis (p=0.570). R2 segments were more vertical in myopic foveoschisis. There was a significant association between lower θ angles at 200 µm temporal and nasal to the fovea and lower BCVA (p<0.001 and p=0.005, respectively). The stiffness of parafoveal Müller cells was predicted to be function of the angle θ , and it grew very rapidly as the θ decreased.ConclusionParafoveal Müller cells in the Henle fibre layer may guarantee structural stability of the parafovea by increasing retinal compliance and resistance to mechanical stress. Small values of the angle θ were related to worse BCVA possibly due to damage to Müller cell processes and photoreceptor’s axons.


2013 ◽  
Vol 521 (11) ◽  
pp. 2439-2453 ◽  
Author(s):  
Jacqueline Chua ◽  
Lisa Nivison-Smith ◽  
Erica L. Fletcher ◽  
Stuart Trenholm ◽  
Gautam B. Awatramani ◽  
...  

2001 ◽  
Vol 6 (1) ◽  
pp. e77 ◽  
Author(s):  
Andreas Bringmann

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