A Comprehensive Review of Mutations in the MERTK Proto-Oncogene

Abstract

Phagocytosis and elimination of shed aged photoreceptor outer segments (POS) by retinal pigment epithelial cells is crucial for photoreceptor function and survival. Genetic studies on a natural animal model of recessive retinal degeneration allowed the identification of MerTK, the gene encoding the surface receptor required for POS internalization. Following this discovery, screenings of DNA samples from patients have revealed that MERTK mutations cause retinal degenerations in humans. MERTK patients present some of the classical symptoms of retinitis pigmentosa, but it is atypical in that the disease develops very early during childhood and the macula is also involved early on. Therefore, the phenotype ought to be qualified as a rod-cone dystrophy. Recently, MERTK has been implicated in various types of cancers and sclerosis. This review identifies the different MERTK mutations known so far and describes associated pathologies.

Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands

“…It remains a mystery how such localized externalization of PtdSer, which is also seen in other cells [76], is achieved. The daily pruning of photoreceptor outer segments is very important: loss-of-function Mertk mutations severely compromise this phagocytosis, and result in inherited forms of retinitis pigmentosa, photoreceptor death, and blindness [73, 77]. …”

Early Events in Retinal Degeneration Caused by Rhodopsin Mutation or Pigment Epithelium Malfunction: Differences and Similarities

“…This genetic defect is a common etiology of autosomal dominant RP (Hartong et al, 2006) and causes defective disc formation, protein misfolding, endoplasmic reticulum stress, and photoreceptor degeneration (Steinberg et al, 1996; Machida et al, 2000; Veleri et al, 2015). The RCS rat bears a mutation of a RPE specific protein: MERTK, which is a tyrosine-protein kinase MER that has been also found in humans with early onset retinal degeneration and Leber Congenital Amaurosis (Gal et al, 2000; Veleri et al, 2015; Parinot and Nandrot, 2016). In this model, photoreceptor degeneration is the result of the failure of the RPE cells to phagocytize outer segment debris (LaVail, 1981; Duncan et al, 2003; Veleri et al, 2015; Parinot and Nandrot, 2016).…”

“…The RCS rat bears a mutation of a RPE specific protein: MERTK, which is a tyrosine-protein kinase MER that has been also found in humans with early onset retinal degeneration and Leber Congenital Amaurosis (Gal et al, 2000; Veleri et al, 2015; Parinot and Nandrot, 2016). In this model, photoreceptor degeneration is the result of the failure of the RPE cells to phagocytize outer segment debris (LaVail, 1981; Duncan et al, 2003; Veleri et al, 2015; Parinot and Nandrot, 2016). In the first animal model, rods are affected first while in the second, as the defect is manifested in the RPE, both rods and cones are affected.…”

A novel MERTK mutation causing retinitis pigmentosa

“…After these initial studies, multiple MERTK mutations were documented in patients with RP. These patients’ disease progression is thought to be more severe than typical RP cases, with early onset in the first decade of life and quickly worsening macular atrophy as seen in our family[15]. …”

“…Photoreceptors continually renew the light-sensitive disks in their outer segments as they bear significant light stress. These shed disks are phagocytized by the RPE [14, 15]. Prior studies have demonstrated that initial photoreceptor outer segment binding to RPE cells is facilitated by the αvβ5 integrin while MERTK is necessary for phagocytosis of the outer segments [16–18].…”