Format

Send to

Choose Destination
Nat Commun. 2015 Jan 9;6:5614. doi: 10.1038/ncomms6614.

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

Author information

1
First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, 120 00 Prague 2, Czech Republic.
2
Faculty of Medicine, Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada H3A 0G1.
3
Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), 110, Ave des Pins Ouest, Montreal, Quebec, Canada H2W 1R7.
4
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.
5
Department of Ophthalmology and Visual Sciences, University of Alberta/Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton, Alberta, Canada AB T5H 3V9.
6
First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University in Prague, 120 00 Prague 2, Czech Republic.
7
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
8
Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, Sao Paulo 04021-001, Brazil.
9
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
10
Department of Ophthalmology, Universidade Federal de São Paulo, Sao Paulo 04021-001, Brazil.
11
Department of Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
12
Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
13
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
14
Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon 97239, USA.
15
Lehrstuhl fuer Neurobiology und Genetik, Universitaet Wuerzburg, 97074 Wuerzburg, Germany.
16
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.
17
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
18
Department of Computer Science, University of Toronto, 10 King's College Road, Toronto, Ontario, Canada M5S 3G4.

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.

PMID:
25574898
PMCID:
PMC4356490
DOI:
10.1038/ncomms6614
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center