RESUMO
Purpose: To report a rare clinical finding of preretinal granules associated with atypical familial exudative vitreoretinopathy (FEVR) and perform a review of the literature. Observations: An asymptomatic 18-year-old male was referred for unilateral peripheral avascular retina evaluation in association with presumed FEVR. He was first noted to have white preretinal granules on fundus examination at five years of age. The lesions remained unchanged over the subsequent years. Genetic testing did not reveal a pathogenic or likely pathogenic variant in a known FEVR gene. A review of the literature revealed five other cases of FEVR with similar findings. Conclusions and Importance: Literature review suggests preretinal granules may present rarely in FEVR. Negative genetic screening of known FEVR genes in our patient with atypical FEVR suggests either a molecularly distinct etiology supporting the rarity of this association with FEVR or, alternatively, the presence of granules in developmental retinal vascular anomalies that are not specific to FEVR. Future study and genetic testing is necessary to better understand the cause of these preretinal granules and the clinical manifestations of FEVR.
RESUMO
Importance: Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR. Objective: To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4. Design, Setting, and Participants: This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function. Main Outcomes and Measures: FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling. Results: The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state. Conclusions and Relevance: Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.
Assuntos
Produtos Biológicos , Oftalmopatias Hereditárias , Perda Auditiva Neurossensorial , Doenças Retinianas , DNA/genética , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Vitreorretinopatias Exsudativas Familiares , Feminino , Receptores Frizzled/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Mutação , Linhagem , Doenças Retinianas/diagnósticoRESUMO
The two-peptide bacteriocins produced by Gram-positive bacteria require two different peptides, present in equimolar amounts, to elicit optimal antimicrobial activity. Producer organisms are protected from their bacteriocin by a dedicated immunity protein. The immunity proteins for two-peptide bacteriocins contain putative transmembrane domains (TMDs) and might therefore be associated with the membrane. The immunity protein CbnZ for the two-peptide bacteriocin carnobacteriocin XY (CbnXY) was identified by heterologously expressing the cbnZ gene in sensitive host strains. Using protein topology prediction methods and the dual pho-lac reporter system, we mapped out the membrane topology of CbnZ, along with those of the immunity proteins LagC and LciM for the two-peptide bacteriocins lactococcin G and lactococcin MN, respectively. Our results reveal wide structural variety between these immunity proteins that can contain as little as one TMD or as many as four TMDs.