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

TitleMutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.
Publication TypeJournal Article
Year of Publication2015
AuthorsKmoch, S, Majewski, J, Ramamurthy, V, Cao, S, Fahiminiya, S, Ren, H, MacDonald, IM, Lopez, I, Sun, V, Keser, V, Khan, A, Stránecký, V, Hartmannová, H, Přistoupilová, A, Hodaňová, K, Piherová, L, Kuchař, L, Baxová, A, Chen, R, Barsottini, OGP, Pyle, A, Griffin, H, Splitt, M, Sallum, J, Tolmie, JL, Sampson, JR, Chinnery, P, Banin, E, Sharon, D, Dutta, S, Grebler, R, Helfrich-Foerster, C, Pedroso, JL, Kretzschmar, D, Cayouette, M, Koenekoop, RK
Corporate AuthorsCare4Rare Canada
JournalNat Commun
Date Published2015 Jan 09
KeywordsAmino Acid Sequence, Animals, Blindness, Child, Child, Preschool, Drosophila, Female, Humans, Male, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Phospholipases, Phospholipids, Retina, Retinal Degeneration, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Spectrometry, Mass, Electrospray Ionization

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.

Alternate JournalNat Commun
PubMed ID25574898
PubMed Central IDPMC4356490
Grant ListR01 NS047663 / NS / NINDS NIH HHS / United States
EY018571-05 / EY / NEI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
EY022356-01 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
NS047663-09 / NS / NINDS NIH HHS / United States
MRC_MR/K000608/1 / / Medical Research Council / United Kingdom
R01 EY018571 / EY / NEI NIH HHS / United States
WT101876 / WT / WETP NIH HHS / United States

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