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

Kmoch, Stanislav; Majewski, Jacek; Ramamurthy, Vasanth; Cao, Shenghao; Fahiminiya, Somayyeh; Ren, Haitao; MacDonald, Ian M.; López, Irma; Sun, Vincent; Keser, Vafa; Khan, Ayesha; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Hodaňová, Kateřina; Piherová, Lenka; Kuchař, Ladislav; Baxová, A; Chen, R; Barsottini, Orlando Graziani Póvoas; Pyle, Angela; Griffin, Helen; Splitt, Miranda; Sallum, Juliana Maria Ferraz; Tolmie, John; Sampson, Julian R.; Chinnery, Patrick F.; Canada, Care Rare; Banin, Eyal; Sharon, Dror; Dutta, S. K.; Grebler, Rudi; Helfrich-Foerster, Charlotte; Pedroso, José Luiz; Kretzschmar, Doris; Cayouette, Michel; Koenekoop, Robert K.

doi:10.1038/ncomms6614

Cited by 81 publications

(65 citation statements)

References 36 publications

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“…Some exemplary clusters of shared or interacting pathways underlying ASS diseases are: Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ). Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 . Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

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Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

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Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

“…Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ).…”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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“…Among the syndromes associated with mutations in PNPLA6 are: Gordon Holmes ( 22,23 ) and Boucher-Neuhauser ( 23 ), characterized by early-onset ataxia and hypogonadism; Oliver-McFarlane ( 24 ), characterized by trichomegaly, congenital hypopituitarism, retinal degeneration, and choroidal atrophy; Laurence-Moon ( 24 ), characterized by progressive spinocerebellar ataxia and spastic paraplegia; and photoreceptor degeneration and childhood blindness ( 25 ). An NTE-related iPLA 2 (PNPLA7) awaits further characterization ( 9, 10 ).…”

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confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

158

170

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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“…It has recently been established that mutations in the particular region of the neuropathy target esterase (NTE) gene coding for the catalytic domain of the NTE protein cause an autosomal-recessive form of HSP (SPG39) Gordon-Holmes syndrome, Boucher-Neuhäuser syndrome, Laurence-Moon syndrome, Oliver-McFarlane syndrome, and Leber's congenital amarosis [1][2][3][4]. Initially, NTE was found in human brain homogenates as an enzyme, the activity of which could be inhibited by organophosphates, leading to the development of organophosphorus compound-induced delayed neuropathy (OPIDN) [5].…”

Section: Introductionmentioning

confidence: 99%

Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

Ryabova¹,

Matiytsiv²,

Trush³

et al. 2018

Drosophila Melanogaster - Model for Recent Advances in Genetics and Therapeutics

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Neuropathy target esterase (NTE) is a molecular target for the organophosphorus compound-induced delayed neuropathy (OPIDN) and also one of the genetic factors responsible for the development of the hereditary spastic paraplegia (HSP), characterized by axon degeneration of motoneurons causing progressive lower-limb spastic paralysis. Both HSP and OPIDN are characterized by the distal axonopathy. The molecular mechanisms underlying the axonopathy involved in HSP and OPIDN are poorly understood. In order to have a beter understanding of the mechanisms that NTE is involved in, we used one of the homologs, human NTE. Swiss cheese (sws) is a Drosophila melanogaster ortholog of NTE with 39% homology. Mutations in sws as it was shown before lead to age-dependent neurodegeneration, structure alteration of glia cells, and reduced insect life span. To study SWS functions, we used the system of the third-instar larval neuromuscular junctions of D. melanogaster. In this study, we show that mutations in sws (sws 1 and sws 76−1) and SWS knockdown alter neuromuscular junction's morphology and synaptic microtubules organization.

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

Cited by 81 publications

References 36 publications

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

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