title: PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.
abstract: Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.
authors.affiliation: 1 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.forename: Charles Marques
authors.initials: CM
authors.lastname: Lourenco
authors.forename: Marie
authors.initials: M
authors.lastname: Coutelier
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Adriana
authors.initials: A
authors.lastname: Rebelo
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Christoph
authors.initials: C
authors.lastname: Kernstock
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Marcos M
authors.initials: MM
authors.lastname: Lima-Martínez
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Wilson
authors.initials: W
authors.lastname: Marques
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
mesh_terms: D000328:Adult; D001259:Ataxia / Q000209:etiology / Q000235:genetics; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D004247:DNA / Q000235:genetics; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D010740:Phospholipases / Q000235:genetics*; D058499:Retinal Dystrophies / Q000235:genetics* / Q000503:physiopathology; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000503:physiopathology; D000217:Acyltransferases
chemical_list: D004247:DNA; D007987:Gonadotropin-Releasing Hormone; D010740:Phospholipases; C586915:PNPLA6 protein, human; D000217:Acyltransferases
keywords: ataxia; early onset ataxia; genetics; hereditary spastic paraplegia; hypogonadism; recessive ataxia; retinal degeneration; spastic ataxia; spasticity