Biomedical subjects

Susanne Roosing

Publications and source records attributed to Susanne Roosing.

3 recordsLinked to original sources

PubMed2025

Founder Homozygous Nonsense CREB3 Variant and Variable-Onset Retinal Degeneration.

IMPORTANCE: Uncovering the genetic basis of inherited retinal diseases (IRDs) can enhance both diagnostic accuracy and the development of targeted treatment strategies. OBJECTIVE: To evaluate the association between a homozygous nonsense variant in CREB3 with IRDs. DESIGN, SETTING, AND PARTICIPANTS: Thirteen patients with a clinical diagnosis of retinitis pigmentosa or cone-rod degeneration were analyzed by whole-genome sequencing (WGS) and whole-exome sequencing (WES). Clinically, patients presented with 2 main phenotypes, rod-cone and cone-rod dystrophies, demonstrating variable electrophysiological and fundoscopic findings. Expression analysis was performed on patient-derived skin fibroblasts using the reverse transcription-polymerase chain reaction and Western blot analysis, and by interrogating previously published retinal single-cell RNA sequence data. Immunohistochemistry staining was performed on wild-type mouse retinal sections using an anti-CREB3 antibody. Patients with variable phenotypes of IRDs were recruited from 3 medical centers in Israel and Italy. Ophthalmologists clinically diagnosed patients at the relevant medical centers and referred them for genetic screening. WES and WGS were performed at different national and international centers, and the findings of the previously unreported gene were shared between investigators. EXPOSURES: CREB3 and IRDs. MAIN OUTCOMES AND MEASURES: The main outcome was evidence supporting an association between CREB3 and IRD. Measures included WES, WGS, and immunohistochemistry staining. RESULTS: A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in 13 patients from 4 unrelated families; 12 descendent from North-African Jewish origins and 1 from Italian origins. All patients manifested retinal degeneration with varying ages at onset. In patient-derived fibroblasts, the variant mRNA transcript generated a truncated CREB3 protein. Expression analysis and immunohistochemistry staining revealed CREB3 RNA and protein expression in various retinal cell types, indicating its vital role in photoreceptor function. CONCLUSIONS AND RELEVANCE: This study found an association between CREB3 and IRDs. CREB3 was previously shown to be upregulated following ultraviolet radiation. This might contribute to the extensive clinical variability observed in this relatively large cohort of homozygous patients with the same truncated variant.

Humans↗

PubMed2025

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

PURPOSE: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Humans↗

PubMed2025

Non-coding single-nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa.

PURPOSE: Variants in untranslated genomic regions are difficult to identify as pathogenic but are capable of causing disease by interfering with gene expression. This study aimed to characterize the effect of variants identified in the 5'-untranslated region of EYS in patients with autosomal recessive retinitis pigmentosa (RP). METHODS: Variant screening included gene panels, Sanger, exome, and genome sequencing. Functional validation included an electrophoretic mobility shift assay and various luciferase assays. RESULTS: Patients with RP from 6 EYS biallelic Arab-Muslim families harbored a 5' noncoding EYS variant, c.-453G>T, and 4 harbored a structural variant affecting the 5' noncoding exons. Electrophoretic mobility shift assay analysis revealed an effect on binding of transcription factors for c.-453G>T and a neighboring variant c.-454G>T. Dual luciferase assays using overexpression of various transcription factors showed distinct effects on expression. c.-453G>T was associated with higher luciferase expression with CRX overexpression and c.-454G>C with OTX2 overexpression. In addition, the 2 variants were found to influence translation by affecting upstream initiation codons. Interestingly, visual function of EYS RP patients who harbor c.-453G>T are better than those with biallelic null EYS variants. CONCLUSION: Our analysis revealed both single-nucleotide and structural variants in the EYS promoter as the cause of autosomal recessive RP. These variants may affect EYS expression via a dual mechanism by altering transcription factor binding affinity at the EYS promoter and by affecting upstream open reading frames.

Humans↗