A dominant mutation inMAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium

Abstract

Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration.

Measuring the Contributions of Basal Laminar Deposit and Bruch's Membrane in Age-Related Macular Degeneration

“…These include Sorsby fundus dystrophy (TIMP3), 14,65 late-onset retinal degeneration (C1QTNF5) , 66,67 Malattia Leventinese/ Doyne's honeycomb retinal dystrophy (EFEMP1), 50,68,69 dense deposit disease / membranoproliferative glomerulonephritis type II (C3 / CFH), 70,71 and possibly Martinique crinkled retinal pigment epitheliopathy (MAPKAP3). [72][73][74] These genes are distinct from those impacting the three-layer BrM (pseudoxanthoma elasticum, ABCC6). 75 BLamD in AMD and C1QTNF5 disease contain histochemically-and ultrastructurally-identified lipid and apolipoprotein B immunoreactivity, thus implicating BLamD as a lipid retentive matrix.…”

BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure

“…The RPE has a key role in maintaining the metabolically active environment of the subretinal space ( 25 , 26 , 49 ). Due to the dynamic relationship with adjacent retinal layers, mutations in RPE-specific genes often adversely affect the neighboring sensory neurons, leading to loss of visual function and PR degeneration ( 50 – 52 ). Mutations in BEST1 are known to disrupt transepithelial ion and fluid transport in response to abnormal levels of intracellular calcium ( 11 – 13 ).…”

Suppression of migration and invasion by taraxerol in the triple-negative breast cancer cell line MDA-MB-231 via the ERK/Slug axis

“…Therefore, ERK1 and ERK2 are often collectively referred to as ERK [ 22 ]. ERK is usually located in the nucleus and is transferred to the cytoplasm after being phosphorylated under various stress states [ 23 ]. ERK is basically activated by dual phosphorylation at threonine and tyrosine sites [ 24 , 25 ], hence, the protein tyrosine phosphatase activity predicted by GO enrichment analysis is necessary for ERK activation [ 26 ].…”