PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum
| Autor: | Tobias B. Haack, Didier Hannequin, Amjad Farooq, Michael A. Gonzalez, Tim M. Strom, Adriana P. Rebelo, Alexandra Durr, Wilson Marques, Christoph Kernstock, Charles Marques Lourenço, Stephan Züchner, Ludger Schöls, Holger Prokisch, Rebecca Schüle, Giovanni Stevanin, Matthis Synofzik, Marcos M. Lima-Martínez, Marie Coutelier |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Models Molecular physiopathology [Spinocerebellar Ataxias] medicine.disease_cause Gonadotropin-Releasing Hormone physiopathology [Heredodegenerative Disorders Nervous System] genetics [Exome] Exome genetics [Spinocerebellar Ataxias] Exome sequencing Genetics Mutation etiology [Ataxia] genetics [Cerebellar Ataxia] genetics [Ataxia] Middle Aged genetics [Retinal Dystrophies] ddc physiology [Mutation] Phospholipases Spinocerebellar ataxia Heredodegenerative Disorders Nervous System Female medicine.symptom physiopathology [Cerebellar Ataxia] ataxia early onset ataxia genetics hereditary spastic paraplegia hypogonadism recessive ataxia retinal degeneration spastic ataxia spasticity Adult Ataxia genetics [Heredodegenerative Disorders Nervous System] Cerebellar Ataxia genetics [Phospholipases] Hereditary spastic paraplegia genetics [Hypogonadism] genetics [Mutation] Biology PNPLA6 protein human physiopathology [Hypogonadism] physiopathology [Retinal Dystrophies] genetics [Spastic Paraplegia Hereditary] Retinal Dystrophies genetics [Gonadotropin-Releasing Hormone] medicine Spinocerebellar Ataxias Humans Family ddc:610 Boucher Neuhäuser syndrome genetics [DNA] Cerebellar ataxia Spastic Paraplegia Hereditary Hypogonadism Original Articles DNA deficiency [Gonadotropin-Releasing Hormone] medicine.disease Neurology (clinical) |
| Zdroj: | Brain 137(1), 69-77 (2013). doi:10.1093/brain/awt326 Brain 137, 69-77 (2014) |
| DOI: | 10.1093/brain/awt326 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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