Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

] Cellular Neurobiology Research Unit Institut de recherches cliniques de Montréal 110 Ave des Pins Ouest Montreal Quebec Canada H2W 1R7 [2] Departement de Médecine Université de Montréal Montreal Quebec Canada H3T 1P1 [3] Division of Experimental Medicine Department of Anatomy and Cell Biology McGill University Montreal Quebec Canada H3A 2B2

] McGill University 845 Sherbrooke Street West Montreal Quebec Canada H3A 0G4 [2] McGill Ocular Genetics Laboratory; Departments of Paediatric Surgery Human Genetics and Ophthalmology Montreal Children's Hospital McGill University Health Centre 2300 Tupper Montreal Quebec Canada H3H 1P3

1st Faculty of Medicine Institute for Inherited Metabolic Disorders Charles University Prague 120 00 Prague 2 Czech Republic

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague 120 00 Prague 2 Czech Republic

Cellular Neurobiology Research Unit Institut de recherches cliniques de Montréal 110 Ave des Pins Ouest Montreal Quebec Canada H2W 1R7

Department of Clinical Genetics Southern General Hospital Glasgow G51 4TF UK

Department of Ophthalmology and Visual Sciences University of Alberta Royal Alexandra Hospital 10240 Kingsway Avenue Edmonton Alberta Canada AB T5H 3V9

Department of Ophthalmology Hadassah Hebrew University Medical Center Jerusalem 91120 Israel

Department of Ophthalmology Universidade Federal de São Paulo Sao Paulo 04021 001 Brazil

Division of General Neurology and Ataxia Unit Department of Neurology Universidade Federal de São Paulo Sao Paulo 04021 001 Brazil

Faculty of Medicine Department of Human Genetics McGill University and Genome Quebec Innovation Center Montreal Quebec Canada H3A 0G1

Human Genome Sequencing Center Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Houston Texas 77030 USA

Institute of Genetic Medicine Newcastle University Newcastle upon Tyne NE1 3BZ UK

Institute of Medical Genetics Cardiff University School of Medicine Cardiff CF14 4XN UK

Lehrstuhl fuer Neurobiology und Genetik Universitaet Wuerzburg 97074 Wuerzburg Germany

Oregon Institute of Occupational Health Sciences Oregon Health and Science University Portland Oregon 97239 USA

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