title: A dominant mutation in MAPKAPK3, 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.
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France, isabelannemeunier@yahoo.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France, Mitochondrial Medicine Research Center, University of Angers, CNRS 6214, INSERM U1083, Angers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bocquet
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Baudoin
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Piro-Megy
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cubizolle
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Quilès
authors.affiliation: Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France.
authors.forename: Albert
authors.initials: A
authors.lastname: Jean-Charles
authors.affiliation: Imaging and Laser Center of Paris, Department of Ophthalmology, Intercity Hospital and University Paris, Creteil, France.
authors.forename: Salomon Yves
authors.initials: SY
authors.lastname: Cohen
authors.affiliation: Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France.
authors.forename: Harold
authors.initials: H
authors.lastname: Merle
authors.affiliation: Department of Ophthalmology, Lariboisiere Hospital, AP-HP and University Paris 7-Sorbonne Paris, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gaudric
authors.affiliation: Center for Structural Biochemistry Montpellier, INSERM U1054-CNRS UMR5048, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Labesse
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Manes
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Péquignot
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France, Institute for Neurosciences, CRIC/IURC, Montpellier, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Cazevieille
authors.affiliation: CHRU Lille, Biochemistry and Molecular Biology Department, University Lille North, Lille, France.
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Dhaenens
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Fichard
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany and.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ronkina
authors.affiliation: MRC Protein Phosphorylation Unit, Dundee, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Arthur
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
mesh_terms: D000328:Adult; D017668:Age of Onset; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D016570:Bruch Membrane / Q000378:metabolism* / Q000473:pathology; D059472:Exome; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D058499:Retinal Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D016415:Sequence Alignment; D035781:Siblings; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases