Severe Familial Exudative Vitreoretinopathy, Congenital Hearing Loss, and Developmental Delay in a Child With Biallelic Variants in FZD4.

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.

Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy.

Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.

Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression.

Heterozygous mutations in the UBIAD1 gene cause Schnyder corneal dystrophy characterized by abnormal cholesterol and phospholipid deposits in the cornea. Ubiad1 protein was recently identified as Golgi prenyltransferase responsible for biosynthesis of vitamin K2 and CoQ10, a key protein in the mitochondrial electron transport chain. Our study shows that silencing UBIAD1 in cultured human hepatocellular carcinoma cells causes dramatic morphological changes and cholesterol storage in the mitochondria, emphasizing an important role of UBIAD1 in mitochondrial function.

Choline transport activity regulates phosphatidylcholine synthesis through choline transporter Hnm1 stability.

Choline is a precursor for the synthesis of phosphatidylcholine through the CDP-choline pathway. Saccharomyces cerevisiae expresses a single high affinity choline transporter at the plasma membrane, encoded by the HNM1 gene. We show that exposing cells to increasing levels of choline results in two different regulatory mechanisms impacting Hnm1 activity. Initial exposure to choline results in a rapid decrease in Hnm1-mediated transport at the level of transporter activity, whereas chronic exposure results in Hnm1 degradation through an endocytic mechanism that depends on the ubiquitin ligase Rsp5 and the casein kinase 1 redundant pair Yck1/Yck2. We present details of how the choline transporter is a major regulator of phosphatidylcholine synthesis.