Pigmentation and vision: Is GPR143 in control?

Abstract

Albinism, typically characterized by decreased melanin synthesis, is associated with significant visual deficits owing to developmental changes during neurosensory retina development. All albinism is caused by genetic mutations in a group of diverse genes including enzymes, transporters, G-protein coupled receptor. Interestingly, these genes are not expressed in the neurosensory retina. Further, regardless of cause of albinism, all forms of albinism have the same retinal pathology, the extent of which is variable. In this review, we explore the possibility that this similarity in retinal phenotype is because all forms of albinism funnel through the same final common pathway. There are currently seven known genes linked to the seven forms of ocular cutaneous albinism. These types of albinism are the most common, and result in changes to all pigmented tissues (hair, skin, eyes). We will discuss the incidence and mechanism, where known, to develop a picture as to how the mutations cause albinism. Next, we will examine the one form of albinism which causes tissue-specific pathology, ocular albinism, where the eye exhibits the retinal albinism phenotype despite near normal melanin synthesis. We will discuss a potential way to treat the disease and restore normal retinal development. Finally, we will briefly discuss the possibility that this same pathway may intersect with the most common cause of permanent vision loss in the elderly.

Phenylthiourea Binding to Human Tyrosinase-Related Protein 1

“…Mutations of the genes that code for these proteins may lead to loss of skin pigmentation, which in turn has been linked to an increased incidence of carcinoma [2]. In addition, loss of melanin is often (but not always) associated with abnormal development of the retina, which causes severe visual defects [3]. The precise relation between melanin biosynthesis and eye development has not yet been established, although the tyrosine hydroxylation product L-3,4-dihydroxyphenylalanine (L-DOPA) has been hypothesized to serve as the link [3].…”

A G-Protein Coupled Receptor and Macular Degeneration

“…As stated previously, there is evidence that RPE support for the neurosensory retina must be paracrine in nature, because the cells of the neural retina do not express the pigmentation pathway genes [20]. With respect to GPR143, this argument suggests that GPR143 signaling controls RPE paracrine release of something critical for retinal development and survival, because of the noted sensory retinal developmental defects when GPR143 is mutated, as in ocular albinism.…”

“…Albinism is a genetic disease and can affect eyes, hair, and skin, which is ocular cutaneous albinism (OCA), or just the eyes, which is ocular albinism (OA). OCA1-7 occur due to mutations in 7 genes with a variety of functions, including several enzymes and some small molecule transporters directly responsible for melanin synthesis (for a review, see [20]). OA is more specific and is caused by mutations in a single G-protein coupled receptor (GPCR) expressed in pigmented cells, GPR143.…”

“…Interestingly, regardless of the genetic cause of albinism, OCA, or OA, the retinal defects are quite similar, suggesting that the underlying defect in RPE melanin accumulation is not proximal to the associated sensory retina alterations. The retinal neurons affected never express any of the genes linked to albinism, so a paracrine factor from the RPE is indicated [20]. While mechanistic defects in the ability to synthesize melanin are easy to grasp, for example in albinism caused by mutated tyrosinase, the downstream effects on retinal development are not obvious.…”

Conversations with Ray Guillery on albinism: linking Siamese cat visual pathway connectivity to mouse retinal development

“…However, attempts to correct visual defects in humans with Levodopa were ineffective (Summers et al ., ), likely because the treatments were done well after RGC neurogenesis. Other experiments have argued that L‐Dopa is a ligand for the orphan GPCR on the melanosome surface encoded by the OA gene (Lopez et al ., ; McKay, ). These latter studies point to factors relevant to maintenance and health of mature RPE, and have not elucidated the relationship between factors in the RPE during embryogenesis and the specification of ipsi vs. contra RGCs.…”