No abstract

At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood. In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T > A, p.Ile114Asn. This work demonstrates how in silico modeling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

In the seven sites audited, compliance with national guidance was entirely appropriate in terms of therapy initiation; however, the requirement to discontinue etanercept in responders was rarely followed. Similarly, discontinuation of biologicals in nonresponders was not routine practice. This may indicate a reluctance of both patients and clinicians to withdraw an at least partly effective therapy from these refractory patients.

Background: Floppy eyelid syndrome (FES) is a common and underdiagnosed condition characterized by eyelid hyperlaxity with reactive palpebral conjunctivitis that can cause ocular irritation. It may be associated with meibomian gland dysfunction (MGD) and secondary tarsal curling, resulting in upper eyelid meibomian gland inversion (MGI) in the absence of obvious marginal entropion.Purpose: To highlight the possible significance of MGI in patients with FES and report findings and outcomes in patients with concomitant MGI and FES undergoing correction of MGI with or without upper eyelid horizontal tightening.Methods: Retrospective, 5-year, noncomparative, singlecenter study of patients with FES and MGI, treated with MGI correction, with or without upper eyelid horizontal tightening, under the supervision of a single surgeon. Preoperative symptoms, surgical outcomes, complication rates, and postoperative symptoms were recorded.Results: A total of 13 eyes of 9 patients were treated with MGI surgery over the study period. Seven were male. Mean age at the surgery was 63 (range 42-81) years. Two OSs, 3 ODs, and 4 OUs were treated. All patients were "cotton-tip test" positive, and 77% (10/13) had MGI-related superior corneal fluorescein staining. Three patients (33%) had previous standard tightening procedures with recurrence of symptoms within 5 to 24 (mean 16) months. Repeat horizontal tightening had been considered in all these cases before referral to our unit. Mean follow-up was 20 months. Eight patients (88.9%) had improvement of symptoms (n = 3, full resolution; n = 5, partial resolution). All patients demonstrated restoration of the normal anatomical position of the meibomian glands. Superior punctate staining resolved in all eyes. Conclusion:This study provides a proof of concept that upper eyelid MGI can be present and symptomatic in patients with FES. It may help explain cases where symptoms persist or recur early following standard upper eyelid horizontal tightening. Where superior corneal punctate staining and a positive cotton-tip test exist, surgical correction of MGI, alongside horizontal tightening, may provide better, and longerlasting symptomatic relief. This study provides evidence for the need for a prospective study to evaluate the contribution of MGI in patients with FES.