Human iPSC derived disease model of MERTK-associated retinitis pigmentosa

被引：44

作者：

Lukovic, Dunja ^{[1
]}

Artero Castro, Ana ^{[1
]}

Garcia Delgado, Ana Belen ^{[1
]}

Martin Bernal, Maria de los Angeles ^{[1
]}

Luna Pelaez, Noelia ^{[1
]}

Diez Lloret, Andrea ^{[1
]}

Perez Espejo, Rocio ^{[1
]}

Kamenarova, Kunka ^{[1
]}

Fernandez Sanchez, Laura ^{[4
]}

Cuenca, Nicolas ^{[4
]}

Corton, Marta ^{[5
,6
]}

Avila Fernandez, Almudena ^{[5
,6
]}

Sorkio, Anni ^{[7
]}

Skottman, Heli ^{[7
]}

Ayuso, Carmen ^{[5
,6
]}

Erceg, Slaven ^{[1
,2
,3
]}

Bhattacharya, Shomi S. ^{[1
]}

机构：

[1] CABIMER Ctr Andaluz Biol Mol & Med Regenerat, Seville 41092, Spain

[2] ISCIII, Res Ctr Principe Felipe, Stem Cell Therapies Neurodegenerat Dis Lab, Valencia 46012, Spain

[3] ISCIII, Res Ctr Principe Felipe, Natl Stem Cell Bank Valencia Node, Biomol & Bioinformat Resources Platform PRB2, Valencia 46012, Spain

[4] Univ Alicante, Dept Physiol Genet & Microbiol, E-03080 Alicante, Spain

[5] IIS Fdn Jimenez Diaz, Dept Genet & Genom, Madrid 28040, Spain

[6] ISCIII, Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain

[7] Univ Tampere, BioMediTech, Tampere 33520, Finland

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

芬兰科学院;

关键词：

PLURIPOTENT STEM-CELLS; ROD-CONE DYSTROPHY; PRECLINICAL MODEL; SITE MUTATION; GENE; PHAGOCYTOSIS; GENERATION; EPITHELIUM; ADHESION; PROTEIN;

D O I：

10.1038/srep12910

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 39 条

[1] Novel splice donor site mutation in MERTK gene associated with retinitis pigmentosa [J].

Brea-Fernandez, A. J. ;

Pomares, E. ;

Brion, M. J. ;

Marfany, G. ;

Blanco, M. J. ;

Sanchez-Salorio, M. ;

Gonzalez-Duarte, R. ;

Carracedo, A. .

BRITISH JOURNAL OF OPHTHALMOLOGY, 2008, 92 (10) :1419-1423

[2] Genetic Dissection of TAM Receptor-Ligand Interaction in Retinal Pigment Epithelial Cell Phagocytosis [J].

Burstyn-Cohen, Tal ;

Lew, Erin D. ;

Traves, Paqui G. ;

Burrola, Patrick G. ;

Hash, Joseph C. ;

Lemke, Greg .

NEURON, 2012, 76 (06) :1123-1132

[3] Synergistic Interaction of Tubby and Tubby-Like Protein 1 (Tulp1) [J].

Caberoy, Nora Blanca .

RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY, 2014, 801 :503-509

[4] Protective Effects of Human iPS-Derived Retinal Pigment Epithelium Cell Transplantation in the Retinal Dystrophic Rat [J].

Carr, Amanda-Jayne ;

Vugler, Anthony A. ;

Hikita, Sherry T. ;

Lawrence, Jean M. ;

Gias, Carlos ;

Chen, Li Li ;

Buchholz, David E. ;

Ahmado, Ahmad ;

Semo, Ma'ayan ;

Smart, Matthew J. K. ;

Hasan, Shazeen ;

da Cruz, Lyndon ;

Johnson, Lincoln V. ;

Clegg, Dennis O. ;

Coffey, Pete J. .

PLOS ONE, 2009, 4 (12)

[5]

Carr AJ, 2009, MOL VIS, V15, P283

[6] Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation [J].

Chen, J ;

Carey, K ;

Godowski, PJ .

ONCOGENE, 1997, 14 (17) :2033-2039

[7] Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat [J].

D'Cruz, PM ;

Yasumura, D ;

Weir, J ;

Matthes, MT ;

Abderrahim, H ;

LaVail, MM ;

Vollrath, D .

HUMAN MOLECULAR GENETICS, 2000, 9 (04) :645-651

[8] An RCS-like retinal dystrophy phenotype in Mer knockout mice [J].

Duncan, JL ;

LaVail, MM ;

Yasumura, D ;

Matthes, MT ;

Yang, HD ;

Trautmann, N ;

Chappelow, AV ;

Feng, W ;

Earp, HS ;

Matsushima, GK ;

Vollrath, D .

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2003, 44 (02) :826-838

[9] Phagocytosis of rod outer segments by retinal pigment epithelial cells requires alpha v beta 5 integrin for binding but not for internalization [J].

Finnemann, SC ;

Bonilha, VL ;

Marmorstein, AD ;

RodriguezBoulan, E .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (24) :12932-12937

[10] Focal adhesion kinase signaling promotes phagocytosis of integrin-bound photoreceptors [J].

Finnemann, SC .

EMBO JOURNAL, 2003, 22 (16) :4143-4154

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