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

Meunier Isabelle, Lenaers Guy, Bocquet Béatrice, Baudoin Corinne, Piro-Megy Camille, Cubizolle Aurélie, Quilès Mélanie, Jean-Charles Albert, Cohen Salomon Yves, Merle Harold, Gaudric Alain, Labesse Gilles, Manes Gael, Péquignot Marie, Cazevieille Chantal, Dhaenens Claire-Marie, Fichard Agnès, Ronkina Natalia, Arthur Simon J., Gaestel Matthias, Hamel Christian P.. 2016. A dominant mutation inMAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Human Molecular Genetics, 25 (5) : 916-926.

Quartile : Q1, Sujet : GENETICS & HEREDITY / Quartile : Q1, Sujet : BIOCHEMISTRY & MOLECULAR BIOLOGY

Résumé : 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.

Mots-clés Agrovoc : epithelium, variation génétique, rétine, mutation, maladie de l'oeil, hérédité

Mots-clés géographiques Agrovoc : France, Martinique

Agences de financement hors UE : Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Agence Nationale de la Recherche

Auteurs et affiliations

• Meunier Isabelle, Université de Montpellier (FRA) - auteur correspondant
• Lenaers Guy, Université de Montpellier (FRA)
• Bocquet Béatrice, Université de Montpellier (FRA)
• Baudoin Corinne, Université de Montpellier (FRA)
• Piro-Megy Camille, Université de Montpellier (FRA) ORCID: 0009-0007-1275-2612
• Cubizolle Aurélie, Université de Montpellier (FRA)
• Quilès Mélanie, Université de Montpellier (FRA)
• Jean-Charles Albert, University Hospital of Fort de France (MTQ)
• Cohen Salomon Yves, Université Paris-Est Créteil Val-de-Marne (FRA)
• Merle Harold, University Hospital of Fort de France (MTQ)
• Gaudric Alain, Université Paris-Sorbonne (FRA)
• Labesse Gilles, CNRS (FRA)
• Manes Gael, Université de Montpellier (FRA)
• Péquignot Marie, Université de Montpellier (FRA)
• Cazevieille Chantal, Université de Montpellier (FRA)
• Dhaenens Claire-Marie, Université de Lille (FRA)
• Fichard Agnès, Université de Montpellier (FRA)
• Ronkina Natalia, Hannover Medical School (DEU)
• Arthur Simon J., MRC Protein Phosphorylation Unit (GBR)
• Gaestel Matthias, Hannover Medical School (DEU)
• Hamel Christian P., Université de Montpellier (FRA)

Source : Cirad-Agritrop (https://agritrop.cirad.fr/611325/)

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