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.
| Original language | English |
|---|---|
| Pages (from-to) | 69-77 |
| Number of pages | 9 |
| Journal | Brain |
| Volume | 137 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2014 |
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Keywords
- ataxia
- early onset ataxia
- genetics
- hereditary spastic paraplegia
- hypogonadism
- recessive ataxia
- retinal degeneration
- spastic ataxia
- spasticity
ASJC Scopus subject areas
- Clinical Neurology
- Arts and Humanities (miscellaneous)
Cite this
PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. / Synofzik, Matthis; Gonzalez, Michael A.; Lourenco, Charles Marques; Coutelier, Marie; Haack, Tobias B.; Rebelo, Adriana; Hannequin, Didier; Strom, Tim M.; Prokisch, Holger; Kernstock, Christoph; Durr, Alexandra; Schöls, Ludger; Lima-Martínez, Marcos M.; Farooq, Amjad; Schüle, Rebecca; Stevanin, Giovanni; Marques, Wilson; Zuchner, Stephan L.
In: Brain, Vol. 137, No. 1, 01.01.2014, p. 69-77.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum
AU - Synofzik, Matthis
AU - Gonzalez, Michael A.
AU - Lourenco, Charles Marques
AU - Coutelier, Marie
AU - Haack, Tobias B.
AU - Rebelo, Adriana
AU - Hannequin, Didier
AU - Strom, Tim M.
AU - Prokisch, Holger
AU - Kernstock, Christoph
AU - Durr, Alexandra
AU - Schöls, Ludger
AU - Lima-Martínez, Marcos M.
AU - Farooq, Amjad
AU - Schüle, Rebecca
AU - Stevanin, Giovanni
AU - Marques, Wilson
AU - Zuchner, Stephan L
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
KW - ataxia
KW - early onset ataxia
KW - genetics
KW - hereditary spastic paraplegia
KW - hypogonadism
KW - recessive ataxia
KW - retinal degeneration
KW - spastic ataxia
KW - spasticity
UR - http://www.scopus.com/inward/record.url?scp=84892750162&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892750162&partnerID=8YFLogxK
U2 - 10.1093/brain/awt326
DO - 10.1093/brain/awt326
M3 - Article
C2 - 24355708
AN - SCOPUS:84892750162
VL - 137
SP - 69
EP - 77
JO - Brain
JF - Brain
SN - 0006-8950
IS - 1
ER -