Publications by authors named "Juliette Wohlschlegel"

5 Publications

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DEEP PHENOTYPING AND FURTHER INSIGHTS INTO ITM2B-RELATED RETINAL DYSTROPHY.

Retina 2021 Apr;41(4):872-881

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Purpose: To reappraise the presentation and the course of ITM2B-related retinal dystrophy and give further insights into ITM2B expression in the retina.

Methods: The clinical data of nine subjects with ITM2B-related retinal dystrophy were retrospectively reviewed. The genetic mutation was assessed for its influence on splicing in cultured fibroblasts. The cellular expression of ITM2B within the inner retina was investigated in wild-type mice through mRNA in situ hybridization.

Results: All patients complained of decreased vision and mild photophobia around their twenties-thirties. The peculiar feature was the hyperreflective material on optical coherence tomography within the inner retina and the central outer nuclear layer with thinning of the retinal nerve fiber layer. Although retinal imaging revealed very mild or no changes over the years, the visual acuity slowly decreased with about one Early Treatment Diabetic Retinopathy Study letter per year. Finally, full-field electroretinography showed a mildly progressive inner retinal and cone dysfunction. ITM2B mRNA is expressed in all cellular types of the inner retina. Disease mechanism most likely involves mutant protein misfolding and/or modified protein interaction rather than misplicing.

Conclusion: ITM2B-related retinal dystrophy is a peculiar, rare, slowly progressive retinal degeneration. Functional examinations (full-field electroretinography and visual acuity) seem more accurate in monitoring the progression in these patients because imaging tends to be stable over the years.
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http://dx.doi.org/10.1097/IAE.0000000000002953DOI Listing
April 2021

Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy.

PLoS One 2020 23;15(4):e0231750. Epub 2020 Apr 23.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding affinity. Two sera recognized all isoforms of TRPM1, while one recognized only the two longest isoforms upon immunolocalization studies on overexpressing cells. Similarly, the former two sera reacted with all TRPM1 isoforms on western blot, but an immunoprecipitation enrichment step was necessary to detect all isoforms with the latter serum. In contrast, all sera labelled ON-bipolar cells on Tprm1+/+ but not on Trpm1-/- mouse retina as shown by co-immunolocalization. This confirms that the MAR sera specifically detect TRPM1. Most likely, the anti-TRPM1 autoantibodies of different patients vary in affinity and concentration. In addition, the binding of autoantibodies to TRPM1 may be conformation-dependent, with epitopes being inaccessible in some constructs (truncated polypeptides versus full-length TRPM1) or applications (western blotting versus immunohistochemistry). Therefore, we propose that a combination of different methods should be used to test for the presence of anti-TRPM1 autoantibodies in the sera of MAR patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179873PMC
July 2020

Generation of human induced pluripotent stem cell lines from a patient with ITM2B-related retinal dystrophy and a non mutated brother.

Stem Cell Res 2019 12 5;41:101625. Epub 2019 Nov 5.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, 17 rue Moreau, Paris, F-75012, France; CHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, Paris, F-75012, France. Electronic address:

Human induced pluripotent stem cell (iPSC) lines were generated from fibroblasts of a patient affected with an autosomal dominant retinal dystrophy carrying the mutation c.782A>C, p.Glu261Ala in ITM2B and from an unaffected brother. Three different iPSC lines were generated and characterized from primary dermal fibroblasts of the affected subject and two from the unaffected brother. All iPSC lines expressed the pluripotency markers, were able to differentiate into the three germ layers and presented normal karyotypes. This cellular model will provide a powerful tool to study this retinal dystrophy and better understand the role of ITM2B.
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http://dx.doi.org/10.1016/j.scr.2019.101625DOI Listing
December 2019

Prevalence of Deep-Intronic Variants and Related Phenotype in An Unsolved "One-Hit" Cohort with Stargardt Disease.

Int J Mol Sci 2019 Oct 11;20(20). Epub 2019 Oct 11.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of . Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients' selection for clinical trials.
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http://dx.doi.org/10.3390/ijms20205053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829239PMC
October 2019