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

Lookup NU author(s): Dr Angela Pyle, Dr Helen GriffinORCiD, Dr Miranda Splitt, Professor Patrick Chinnery


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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 photo-receptors 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.

Publication metadata

Author(s): Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, MacDonald IM, Lopez I, Sun V, Keser V, Khan A, Stranecky V, Hartmannova H, Pristoupilova A, Hodanova K, Piherova L, Kuchar L, Baxova 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, Care4Rare Canada

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2015

Volume: 6

Online publication date: 08/01/2015

Acceptance date: 21/10/2014

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/ncomms6614


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Funder referenceFunder name
Canadian Institutes of Health Research
Genome British Columbia
Genome Quebec
Government of Canada through Genome Canada
McLaughlin Centre
Foundation Fighting Blindness Canada
Graduate School of Life Sciences (University of Wuerzburg)
CZ.1.05/1.1.00/02.0109BIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development Fund
OGI-049Ontario Genomics Institute
NT13116-4/2012Ministry of Health of the Czech Republic
NT14015-3/2013Ministry of Health of the Czech Republic
PRVOUK-P24/LF1/3Charles University institutional programmes
UNCE 204011Charles University institutional programmes
SVV2013/266504Charles University institutional programmes