title: Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.
abstract: 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.
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Kmoch
authors.affiliation: Faculty of Medicine, Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada H3A 0G1.
authors.forename: J
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), 110, Ave des Pins Ouest, Montreal, Quebec, Canada H2W 1R7.
authors.forename: V
authors.initials: V
authors.lastname: Ramamurthy
authors.affiliation: 1] 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.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.affiliation: Faculty of Medicine, Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada H3A 0G1.
authors.forename: S
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: 1] 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.
authors.forename: H
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Alberta/Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton, Alberta, Canada AB T5H 3V9.
authors.forename: I M
authors.initials: IM
authors.lastname: MacDonald
authors.affiliation: 1] 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.
authors.forename: I
authors.initials: I
authors.lastname: Lopez
authors.affiliation: 1] 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.
authors.forename: V
authors.initials: V
authors.lastname: Sun
authors.affiliation: 1] 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.
authors.forename: V
authors.initials: V
authors.lastname: Keser
authors.affiliation: 1] 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.
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Stránecký
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: H
authors.initials: H
authors.lastname: Hartmannová
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Přistoupilová
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Hodaňová
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Piherová
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Kuchař
authors.affiliation: First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Baxová
authors.affiliation: Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.affiliation: Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, Sao Paulo 04021-001, Brazil.
authors.forename: O G P
authors.initials: OG
authors.lastname: Barsottini
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: H
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Splitt
authors.affiliation: Department of Ophthalmology, Universidade Federal de São Paulo, Sao Paulo 04021-001, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Sallum
authors.affiliation: Department of Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Tolmie
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: P
authors.initials: P
authors.lastname: Chinnery
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Banin
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Lehrstuhl fuer Neurobiology und Genetik, Universitaet Wuerzburg, 97074 Wuerzburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Grebler
authors.affiliation: Lehrstuhl fuer Neurobiology und Genetik, Universitaet Wuerzburg, 97074 Wuerzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Helfrich-Foerster
authors.affiliation: Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, Sao Paulo 04021-001, Brazil.
authors.forename: J L
authors.initials: JL
authors.lastname: Pedroso
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kretzschmar
authors.affiliation: 1] Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), 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.
authors.forename: M
authors.initials: M
authors.lastname: Cayouette
authors.affiliation: 1] 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.
authors.forename: R K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001766:Blindness / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004330:Drosophila; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010740:Phospholipases / Q000235:genetics* / Q000502:physiology*; D010743:Phospholipids / Q000737:chemistry; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D000217:Acyltransferases
chemical_list: D010740:Phospholipases; D010743:Phospholipids; C586915:PNPLA6 protein, human; D000217:Acyltransferases