Robert B Hufnagel1, Gavin Arno2, Nichole D Hein3, Joshua Hersheson4, Megana Prasad5, Yvonne Anderson6, Laura A Krueger1, Louise C Gregory7, Corinne Stoetzel5, Thomas J Jaworek8, Sarah Hull2, Abi Li4, Vincent Plagnol9, Christi M Willen10, Thomas M Morgan11, Cynthia A Prows1, Rashmi S Hegde12, Saima Riazuddin8, Gregory A Grabowski1, Rudy J Richardson13, Klaus Dieterich14, Taosheng Huang1, Tamas Revesz4, J P Martinez-Barbera7, Robert A Sisk15, Craig Jefferies16, Henry Houlden4, Mehul T Dattani7, John K Fink3, Helene Dollfus17, Anthony T Moore2, Zubair M Ahmed8. 1. Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA. 2. UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK. 3. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. 4. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 5. Laboratoire de génétique Médicale, Université de Strasbourg, FMTS, Strasbourg, France. 6. Department of Paediatrics, Taranaki Base Hospital, New Plymouth, New Zealand Liggins Institute, University of Auckland, Auckland, New Zealand. 7. Developmental Endocrinology Research Group, Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London, UK. 8. Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland, USA. 9. Department of Statistical Genetics, University College London, London, UK. 10. Department of Pediatric Ophthalmology, University of Kentucky, Lexington, Kentucky, USA. 11. Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA. 12. Developmental Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA. 13. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA. 14. Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble and Grenoble Institut des Neurosciences, Equipe Muscle et Pathologie, Grenoble, France. 15. Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA Cincinnati Eye Institute, Cincinnati, Ohio, USA. 16. Department of Paediatric Endocrinology, Starship Children's Hospital, Auckland, New Zealand. 17. Laboratoire de génétique Médicale, Université de Strasbourg, FMTS, Strasbourg, France Centre de référence pour les Affections Rares Ophtalmologiques CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Abstract
BACKGROUND: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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