MFRP
Membrane frizzled-related protein (Membrane-type frizzled-related protein)
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A 4 base pair deletion in a splice donor site of the Mfrp (membrane-type frizzled-related protein) gene, herein referred to as Mfrprd6/rd6, is predicted to lead to the skipping of exon 4 and photoreceptor degeneration in retinal degeneration 6 (rd6) mutant mice. Little, however, is known about the function of the protein or how the mutation causes the degenerative retinal phenotype. Here we examine ultrastructural changes in the retina of Mfrprd6/rd6 mice to determine the earliest effects of the mutation. We also extend the reported observations of the expression pattern of the dicistronic Mfrp/C1qtnf5 message and the localization of these and other retinal pigment epithelium (RPE) and retinal proteins during development and assess the ability of RPE cells to phagocytize outer segments (OSs) in mutant and wild-type (WT) mice. At the ultrastructural level, OSs do not develop normally in Mfrprd6/rd6 mutants. They are disorganized and become progressively shorter as mutant mice age. Additionally, there are focal areas in which there is a reduction of apical RPE microvilli. At P25, the rod electroretinogram (ERG) a-wave of Mfrprd6/rd6 mice is reduced in amplitude by ~50% as are ERG components generated by the RPE. Examination of beta-catenin localization and Fos and Tcf-1 expression, intermediates of the canonical Wnt pathway, showed that they were not different between mutant and WT mice, suggesting that MFRP may operate through an alternative pathway. Finally, impaired OS phagocytosis was observed in Mfrprd6/rd6 mice both in standard ambient lighting conditions and with bright light exposure when compared to WT controls.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Down-Regulation
- Electroretinography
- Embryo, Mammalian
- Embryonic Development
- Eye Proteins
- Gene Deletion
- Gene Expression
- Light
- Membrane Proteins
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Phagocytosis
- Photoreceptor Cells
- Pigment Epithelium of Eye
- Retina
- Retinal Rod Photoreceptor Cells
- Tissue Distribution
Nanophthalmos is a genetic disorder characterized by very small, hyperopic eyes that are without gross structural defects. Recessive nanophthalmos is caused by severe mutations in the MFRP gene, which encodes a Frizzled-related transmembrane protein that is selectively expressed in the retinal pigment epithelium (RPE) and ciliary body. For two MFRP -/- adults, we have obtained records of refraction that begin in early childhood. At the age of 6 months, one patient's eyes already had a refractive error of 12.25 D, and over the next 20 years this slowly increased to 17.50 D. Adults homozygous for null mutations in MFRP have eyes with axial lengths shorter than those of normal newborns. Furthermore, the unusually high curvature of their corneas is consistent with eyes that had been smaller than normal during late fetal development. MFRP protein was first detected at 14 weeks of gestation, when it was restricted to the posterior pole RPE. By 20 weeks gestation, MFRP expression had spread laterally, and was found throughout the RPE. MFRP protein was detected in both posterior and lateral RPE of the adult eye. Embryonic function of the MFRP gene appears necessary for the eye to reach its full size at birth. Its onset of expression in the RPE during mid-gestation suggests that MFRP does not participate in early formation of the optic cup, and is consistent with a role in later growth and development of the eye. Patients without MFRP gene function exhibit no correction of refractive error during childhood, which suggests that this gene is essential for emmetropization, a complex process by which vision regulates axial growth of the eye.
MeSH Terms
- Adult
- Aging
- Embryo, Mammalian
- Embryonic Development
- Eye
- Frameshift Mutation
- Gene Deletion
- Genes, Recessive
- Gestational Age
- Homozygote
- Humans
- Hyperopia
- Infant
- Infant, Newborn
- Lens, Crystalline
- Membrane Proteins
- Microphthalmos
- Ocular Physiological Phenomena
- Pigment Epithelium of Eye
- Refraction, Ocular
- Vision, Ocular