Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

S. Kmoch, J. Majewski, V. Ramamurthy, S. Cao, S. Fahiminiya, H. Ren, I. M. MacDonald, I. Lopez, V. Sun, V. Keser, A. Khan, V. Stránecký, H. Hartmannová, A. Přistoupilová, K. Hodaňová, L. Piherová, L. Kuchař, A. Baxová, R. Chen, O. G. P. Barsottini, A. Pyle, H. Griffin, M. Splitt, J. Sallum, J. L. Tolmie, J. R. Sampson, P. Chinnery, E. Banin, D. Sharon, S. Dutta, R. Grebler, C. Helfrich-Foerster, J. L. Pedroso, D. Kretzschmar (), M. Cayouette () and R. K. Koenekoop ()
Additional contact information
S. Kmoch: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
J. Majewski: Faculty of Medicine, McGill University and Genome Quebec Innovation Center
V. Ramamurthy: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM)
S. Cao: McGill University
S. Fahiminiya: Faculty of Medicine, McGill University and Genome Quebec Innovation Center
H. Ren: McGill University
I. M. MacDonald: University of Alberta/Royal Alexandra Hospital
I. Lopez: McGill University
V. Sun: McGill University
V. Keser: McGill University
A. Khan: McGill University
V. Stránecký: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
H. Hartmannová: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
A. Přistoupilová: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
K. Hodaňová: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
L. Piherová: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
L. Kuchař: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague
A. Baxová: First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University in Prague
R. Chen: Human Genome Sequencing Center, Baylor College of Medicine
O. G. P. Barsottini: Universidade Federal de São Paulo
A. Pyle: Institute of Genetic Medicine, Newcastle University
H. Griffin: Institute of Genetic Medicine, Newcastle University
M. Splitt: Institute of Genetic Medicine, Newcastle University
J. Sallum: Universidade Federal de São Paulo
J. L. Tolmie: Southern General Hospital
J. R. Sampson: Institute of Medical Genetics, Cardiff University School of Medicine
P. Chinnery: Institute of Genetic Medicine, Newcastle University
E. Banin: Hadassah-Hebrew University Medical Center
D. Sharon: Hadassah-Hebrew University Medical Center
S. Dutta: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University
R. Grebler: Lehrstuhl fuer Neurobiology und Genetik, Universitaet Wuerzburg
C. Helfrich-Foerster: Lehrstuhl fuer Neurobiology und Genetik, Universitaet Wuerzburg
J. L. Pedroso: Universidade Federal de São Paulo
D. Kretzschmar: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University
M. Cayouette: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM)
R. K. Koenekoop: McGill University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms6614

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