Human iPSC derived disease model of MERTK-associated retinitis pigmentosa.
Retinitis pigmentosa (RP) represents a genetically heterogeneous group of retinal dystrophies affecting mainly the rod photoreceptors and in some instances also the retinal pigment epithelium (RPE) cells of the retina. Clinical symptoms and disease progression leading to moderate to severe loss of vision are well established and despite significant progress in the identification of causative genes, the disease pathology remains unclear. Lack of this understanding has so far hindered development of effective therapies. Here we report successful generation of human induced pluripotent stem cells (iPSC) from skin fibroblasts of a patient harboring a novel Ser331Cysfs*5 mutation in the MERTK gene. The patient was diagnosed with an early onset and severe form of autosomal recessive RP (arRP). Upon differentiation of these iPSC towards RPE, patient-specific RPE cells exhibited defective phagocytosis, a characteristic phenotype of MERTK deficiency observed in human patients and animal models. Thus we have created a faithful cellular model of arRP incorporating the human genetic background which will allow us to investigate in detail the disease mechanism, explore screening of a variety of therapeutic compounds/reagents and design either combined cell and gene- based therapies or independent approaches.
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Dunja
D
Lukovic
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Ana
A
Artero Castro
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Ana Belen Garcia
AB
Delgado
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
María de los Angeles Martín
Mde L
Bernal
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Noelia
N
Luna Pelaez
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Andrea
A
Díez Lloret
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Rocío
R
Perez Espejo
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Kunka
K
Kamenarova
Department of Physiology, Genetics and Microbiology, University of Alicante, Campus de San Vicente del Raspeig, 0369 Alicante, Spain.
Laura
L
Fernández Sánchez
Department of Physiology, Genetics and Microbiology, University of Alicante, Campus de San Vicente del Raspeig, 0369 Alicante, Spain.
Nicolás
N
Cuenca
1] Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain [2] Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
Marta
M
Cortón
1] Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain [2] Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
Almudena
A
Avila Fernandez
BioMediTech, University of Tampere, Biokatu 12, 33520 Tampere, Finland.
Anni
A
Sorkio
BioMediTech, University of Tampere, Biokatu 12, 33520 Tampere, Finland.
Heli
H
Skottman
1] Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain [2] Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
Carmen
C
Ayuso
1] CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain [2] Stem Cell therapies in Neurodegenerative diseases Lab, and National Stem Cell Bank-Valencia Node, Biomolecular and Bioinformatics Resources Platform PRB2,ISCIII, Research Center "Principe Felipe", c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
Slaven
S
Erceg
CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa), Avda. Americo Vespucio s/n, Parque Científico y Tecnológico Cartuja, 41092, Sevilla, Spain.
Shomi S
SS
Bhattacharya
D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology*; D000076202:c-Mer Tyrosine Kinase
D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase