PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.

Matthis Synofzik, Michael A. Gonzalez, Charles Marques Lourenco, Marie Coutelier, Tobias B. Haack, Adriana Rebelo, Didier Hannequin, Tim M. Strom, Holger Prokisch, Christoph Kernstock, Alexandra Durr, Ludger Schöls, Marcos M. Lima-Martínez, Amjad Farooq, Rebecca Schüle, Giovanni Stevanin, Wilson Marques, Stephan Züchner
Brain. 2013-12-18; 137(1): 69-77
DOI: 10.1093/brain/awt326

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1. Brain. 2014 Jan;137(Pt 1):69-77. doi: 10.1093/brain/awt326. Epub 2013 Dec 19.

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a
broad neurodegenerative spectrum.

Synofzik M(1), Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A,
Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schöls L, Lima-Martínez
MM, Farooq A, Schüle R, Stevanin G, Marques W Jr, Züchner S.

Author information:
(1)1 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical
Brain Research, University of Tübingen, Germany.

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

DOI: 10.1093/brain/awt326
PMCID: PMC3891450
PMID: 24355708 [Indexed for MEDLINE]

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