WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression

Majander, Anna; Jurkutė, Neringa; Burté, Florence; Brock, Kristian; João, Catarina; Huang, Houbin; Neveu, M.; Chan, Choi Mun; Duncan, Holly; Kelly, Simon P.; Burkitt-Wright, Emma; Khoyratty, F.; Lai, Yoon Tse; Subash, Malavika; Chinnery, Patrick F.; Bitner‐Glindzicz, Maria; Arno, Gavin; Webster, Andrew R.; Moore, Anthony T.; Michaelides, Michel; Stockman, Andrew; Robson, Anthony G.; Yu‐Wai‐Man, Patrick

doi:10.1016/j.ajo.2022.04.003

Cited by 17 publications

(9 citation statements)

References 54 publications

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“…These results highlight principles that are important in understanding the genotype-phenotype relationship in Wolfram syndrome. Firstly, it has been previously suggested that a greater number of variants correlates with earlier onset and a more severe presentation of Wolfram Syndrome ( Majander et al, 2022 ). Autosomal dominant variants have previously been associated with Wolfram-like syndrome, a WFS1-related disorder with generally milder phenotypes and unlike Wolfram Syndrome, no decrease in life expectancy ( de Muijnck et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Prior studies have attempted to leverage Wolfram Syndrome genotype information or even protein expression in patient-derived fibroblasts ( Smith et al, 2004 ; Hu et al, 2022 ; Majander et al, 2022 ) as predictors or correlates of clinical severity of Wolfram Syndrome. While these studies have successfully correlated biallelic variants ( Majander et al, 2022 ), variants in specific exons ( Smith et al, 2004 ), and low expression of WFS1 in patient fibroblasts ( Hu et al, 2022 ) with clinical severity of vision impairment and other clinical phenotypes, they all represent smaller cohorts consisting of at most, 37 patients. Consequently, genotype-phenotype correlations made with larger cohorts of patients with Wolfram Syndrome might yield novel insights not just about individual causal variants, but about higher level patterns and “rules” that could provide prognostic information for patients, even for variants that have not yet been observed clinically.…”

Section: Introductionmentioning

confidence: 99%

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Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders

et al. 2023

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Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately.Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants. Missense/in-frame variants were further classified as transmembrane or non-transmembrane based on whether they affected amino acid residues predicted to be in transmembrane domains of WFS1. Statistical analysis was performed using Wilcoxon rank-sum tests with multiple test adjustment applied via the Bonferonni correction.Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by diabetes mellitus and optic atrophy emerging significantly earlier in patients with two nonsense/frameshift variants compared with zero or one nonsense/frameshift variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy among patients with either one or two in-frame variants.Summary/Conclusion: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders

et al. 2023

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“…Because of the role that Wolframin plays in a wide plethora of cellular processes, exploring the impact of WFS1 variants on cell function and survival may represent a crucial step for their association with clinical phenotype. Previous attempts to discover genotype and phenotype correlations led to the classification of WFS1 mutations according to their impact on the protein expression and stability (16, 40, 41). A robust classification of WFS1 genetic variants by disease onset and spectrum and severity of symptoms has been recently published as well (18).…”

Section: Discussionmentioning

confidence: 99%

AWFS1variant disrupting acceptor splice site uncovers the impact of alternative splicing on β cell apoptosis in a patient with Wolfram syndrome

Chimienti,

Torchio,

Siracusano

et al. 2023

Preprint

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Wolfram Syndrome 1 is an inherited condition manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy, variable hearing impairment/deafness, diabetes insipidus, neurologic defects and other psychiatric abnormalities. The causative gene is WFS1, which encodes for a master regulator of several cellular responses, named Wolframin. As over 200 mutations have been reported in association with a great clinical variability, a convincing genotype-phenotype correlation is crucial to deal with disease severity and identify effective therapy. Herein, we investigate a patient carrying the WFS1 mutations c.316-1G>A and c.757A>T. By using iPSC-derived pancreatic β cells from this patient, we demonstrated that the allele carrying the acceptor splice site (ASS) mutation c.316-1G>A originates premature termination codon (PTC)-containing splicing variants, and two ORF-conserving mRNAs leading to N-terminally truncated polypeptides. We found that degradation of PTC-carrying transcripts is regulated by nonsense mediated decay (NMD) and inflammatory stress-induced changes in NMD-related genes result in over-expression of these aberrant WFS1 mRNAs, predisposing β cells to unfolded protein response-independent apoptosis. Following Cas9-mediated recovering of ASS, we retrieved the canonical transcriptional landscape and rescued normal phenotype in patient-derived β cells. Overall, our study provides a model for the characterization of WFS1 mutations, uncovering new therapeutic targets for this rare disease.

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“…A generalised reduction in overall retinal vessel density has been reported on OCT angiography in addition to retinal microvascular impairment at the optic nerve head and macular superficial capillary plexus, with mild retinal degeneration also present, usually in the absence of diabetic retinopathy. OCT imaging has also demonstrated anomalies in lamination at of the outer plexiform layer and microcystoid oedema in the inner nuclear layer in autosomal dominant cases (312)(313)(314). Normal pupillary responses have been described, although and Adie's tonic pupil has been reported in some presentations (300,310,311).…”

Section: 103(c) Wolfram Syndromementioning

confidence: 99%

The Impact of Optic Nerve Disorders on Sleep Wake

Stevenson

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WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression

Cited by 17 publications

References 54 publications

Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders

Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders

AWFS1variant disrupting acceptor splice site uncovers the impact of alternative splicing on β cell apoptosis in a patient with Wolfram syndrome

The Impact of Optic Nerve Disorders on Sleep Wake

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