PMID- 26668131 OWN - NLM STAT- MEDLINE DCOM- 20160712 LR - 20191008 IS - 1468-6244 (Electronic) IS - 0022-2593 (Print) IS - 0022-2593 (Linking) VI - 53 IP - 3 DP - 2016 Mar TI - Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. PG - 180-9 LID - 10.1136/jmedgenet-2015-103338 [doi] AB - BACKGROUND: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. METHODS: Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization--time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. RESULTS: The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. CONCLUSIONS: Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - Davids, Mariska AU - Davids M AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Kane, Megan S AU - Kane MS AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - He, Miao AU - He M AD - Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA The Michael J Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. FAU - Wolfe, Lynne A AU - Wolfe LA AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Li, Xueli AU - Li X AD - Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA The Michael J Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. FAU - Raihan, Mohd A AU - Raihan MA AD - Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA The Michael J Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. FAU - Chao, Katherine R AU - Chao KR AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Bone, William P AU - Bone WP AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Boerkoel, Cornelius F AU - Boerkoel CF AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Gahl, William A AU - Gahl WA AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. FAU - Toro, Camilo AU - Toro C AD - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, Maryland, USA. LA - eng GR - Z99 HG999999/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20151214 PL - England TA - J Med Genet JT - Journal of medical genetics JID - 2985087R RN - EC 2.4.99.- (Sialyltransferases) RN - EC 3.1.1.4 (Group VI Phospholipases A2) RN - EC 3.1.1.4 (PLA2G6 protein, human) RN - Dystonia-Parkinsonism, Adult-Onset SB - IM MH - Adult MH - Cells, Cultured MH - Dystonic Disorders/genetics/*metabolism/*pathology MH - Female MH - Fibroblasts/metabolism/ultrastructure MH - Glycosylation MH - Golgi Apparatus/metabolism/*ultrastructure MH - Group VI Phospholipases A2/*deficiency/genetics/metabolism MH - Humans MH - Infant MH - Male MH - Mutation MH - Neuroaxonal Dystrophies/genetics/*metabolism/*pathology MH - Neurodegenerative Diseases/genetics/metabolism/pathology MH - Parkinsonian Disorders/genetics/*metabolism/*pathology MH - Sialyltransferases/metabolism PMC - PMC5535303 MID - NIHMS884018 OTO - NOTNLM OT - Cell biology OT - Molecular genetics OT - Neuromuscular disease COIS- Competing interests: CFB currently works at University of British Columbia, Vancouver, Canada. EDAT- 2015/12/17 06:00 MHDA- 2016/07/13 06:00 PMCR- 2017/07/31 CRDT- 2015/12/16 06:00 PHST- 2015/06/24 00:00 [received] PHST- 2015/11/09 00:00 [accepted] PHST- 2015/12/16 06:00 [entrez] PHST- 2015/12/17 06:00 [pubmed] PHST- 2016/07/13 06:00 [medline] PHST- 2017/07/31 00:00 [pmc-release] AID - jmedgenet-2015-103338 [pii] AID - 10.1136/jmedgenet-2015-103338 [doi] PST - ppublish SO - J Med Genet. 2016 Mar;53(3):180-9. doi: 10.1136/jmedgenet-2015-103338. Epub 2015 Dec 14.