@article{e2e68fbdf70d484aad2c7d3bc123d834,
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.",
author = "S. Kmoch and J. Majewski and V. Ramamurthy and S. Cao and S. Fahiminiya and H. Ren and Macdonald, {I. M.} and I. Lopez and V. Sun and V. Keser and A. Khan and V. Str{\'a}neck{\'y} and H. Hartmannov{\'a} and {P{\aa} Istoupilov{\'a}}, A. and {Hoda{\AA} ov{\'a}}, K. and L. Piherov{\'a} and L. Kucha{\AA} and A. Baxov{\'a} and R. Chen and Barsottini, {O. G.P.} and A. Pyle and H. Griffin and M. Splitt and J. Sallum and Tolmie, {J. L.} and Sampson, {J. R.} and P. Chinnery and E. Banin and D. Sharon and S. Dutta and R. Grebler and C. Helfrich-Foerster and Pedroso, {J. L.} and D. Kretzschmar and M. Cayouette and Koenekoop, {R. K.} and Kym Boycott and Alex MacKenzie and Michael Brudno and Dennis Bulman and David Dyment",
note = "Funding Information: We sincerely thank the children and parents involved in this study. We acknowledge the crucial support from the Foundation Fighting Blindness Canada (to I.M.M., M.C. and R.K.K.). Further funding came from the Canadian Institutes of Health Research (M.C. and R.K.K.) and NIH (EY022356-01, EY018571-05 and NS047663-09 to R.K.K., R.C. and D.K.). M.C. is a Senior Fellow of the Fonds de recherche du Qu{\'e}bec-Sant{\'e}/ Fondation Antoine-Turmel. S.K. is supported by the Charles University institutional programmes PRVOUK-P24/LF1/3, UNCE 204011 and SVV2013/266504, and by BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund. Specific support was provided by grant NT13116-4/2012 and NT14015-3/2013 from the Ministry of Health of the Czech Republic. R.G. was supported by the Graduate School of Life Sciences (University of Wuerzburg). We gratefully acknowledge the indispensible work of Xia Wang, Hui Wang, Ms Eunice Esteban, Leah Wood MSc, Jonas Tapia RN and Renee Pigeon. We sincerely thank the Care4Rare Canada Steering Committee: Kym Boycott (leader; University of Ottawa), Jan Friedman (co-lead; University of British Columbia), Jacques Michaud (co-lead; Universit{\'e} de Montr{\'e}al), Francois Bernier (University of Calgary), Michael Brudno (University of Toronto), Bridget Fernandez (Memorial University), Bartha Knoppers (McGill University), Mark Samuels (Universit{\'e} de Montr{\'e}al) and Steve Scherer (University of Toronto). This work was funded in part by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research and the Ontario Genomics Institute (OGI-049). Additional funding was provided by Genome Quebec, Genome British Columbia and the McLaughlin Centre. We thank Janet Marcadier (Clinical Coordinator) and Chandree Beaulieu (Project Manager) for their contribution to the infrastructure of the FORGE Canada Consortium. We acknowledge the contribution of the high-throughput sequencing platform of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = jan,
day = "8",
doi = "10.1038/ncomms6614",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}