title: Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.
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.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hufnagel
authors.affiliation: UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nichole D
authors.initials: ND
authors.lastname: Hein
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: Laboratoire de génétique Médicale, Université de Strasbourg, FMTS, Strasbourg, France.
authors.forename: Megana
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Department of Paediatrics, Taranaki Base Hospital, New Plymouth, New Zealand Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Anderson
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Krueger
authors.affiliation: 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.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Gregory
authors.affiliation: Laboratoire de génétique Médicale, Université de Strasbourg, FMTS, Strasbourg, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.affiliation: Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jaworek
authors.affiliation: UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Abi
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Statistical Genetics, University College London, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Pediatric Ophthalmology, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Christi M
authors.initials: CM
authors.lastname: Willen
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Prows
authors.affiliation: Developmental Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.affiliation: Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
authors.affiliation: Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble and Grenoble Institut des Neurosciences, Equipe Muscle et Pathologie, Grenoble, France.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dieterich
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: 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.
authors.forename: J P
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.affiliation: Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA Cincinnati Eye Institute, Cincinnati, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sisk
authors.affiliation: Department of Paediatric Endocrinology, Starship Children's Hospital, Auckland, New Zealand.
authors.forename: Craig
authors.initials: C
authors.lastname: Jefferies
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: 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.
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Fink
authors.affiliation: 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.
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
authors.affiliation: UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001763:Blepharoptosis / Q000201:enzymology* / Q000235:genetics*; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000235:genetics*; D002490:Central Nervous System / Q000473:pathology; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics; D004392:Dwarfism / Q000201:enzymology* / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D006801:Humans; D006983:Hypertrichosis / Q000201:enzymology* / Q000235:genetics*; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics*; D007849:Laurence-Moon Syndrome / Q000201:enzymology* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010740:Phospholipases / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D012160:Retina / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000201:enzymology* / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology; D000217:Acyltransferases
chemical_list: D002265:Carboxylic Ester Hydrolases; D010740:Phospholipases; C586915:PNPLA6 protein, human; D000217:Acyltransferases; C021859:neurotoxic esterase
keywords: Dermatology; Developmental; Genetics; Neuro endocrinology; Ophthalmology