Journal
BRAIN
Volume 137, Issue -, Pages 69-77Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awt326
Keywords
ataxia; recessive ataxia; hypogonadism; retinal degeneration; spastic ataxia; early onset ataxia; spasticity; genetics; hereditary spastic paraplegia
Categories
Funding
- National Institute of Health (NIH) [5R01NS072248, 1R01NS075764, 5R01NS054132, R01-GM083897]
- USylvester Braman Family Breast Cancer Institute
- Interdisciplinary Center for Clinical Research IZKF Tubingen [1970-0-0]
- European Union [PIOF-GA-2012-326681]
- European EUROSCAR project, E-RARE [01GM0807, 01GM0820]
- Deutsche Forschungsgemeinschaft [SCHO754/4-1, SCHO754/5-1]
- German Research Council (BMBF) [01GM0864]
- Fond National de la Recherche Scientifique of Belgium (aspirant fellowship)
- French National Agency for Research
- The Verum Foundation
- Fondation Roger de Spoelberch
- program Investissements d'avenir'' [ANR-10-IAIHU-06]
- E-Rare project GENOMIT [01GM1207]
- German Network for mitochondrial disorders [mitoNET 01GM0867]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM083897] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS072248, R01NS075764, R01NS054132] Funding Source: NIH RePORTER
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Boucher-Neuhauser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhauser 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-Neuhauser 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-Neuhauser 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-Neuhauser 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.
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