PNPLA6 mutations cause Boucher-Neuhäuser 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 L Zuchner

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)69-77
Number of pages9
JournalBrain
Volume137
Issue number1
DOIs
StatePublished - Jan 1 2014

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Mutation
Hereditary Spastic Paraplegia
Exome
Hypogonadism
Ataxia
Neurodegenerative Diseases
Charcot-Marie-Tooth Disease
Neurosecretory Systems
Motor Neurons
Esterases
Cerebellum
Acetylcholine
Neurotransmitter Agents
Reflex
Retina
Phospholipids
Cerebellar Ataxia and Hypogonadotropic Hypogonadism
Causes
Syndrome
Genes

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 journalArticle

Synofzik, M, 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 & Zuchner, SL 2014, 'PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum', Brain, vol. 137, no. 1, pp. 69-77. https://doi.org/10.1093/brain/awt326
Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A et al. PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014 Jan 1;137(1):69-77. https://doi.org/10.1093/brain/awt326
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. / PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. In: Brain. 2014 ; Vol. 137, No. 1. pp. 69-77.
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