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PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.
Brain. 2014 Jan; 137(Pt 1):69-77.B

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.

Authors+Show Affiliations

1 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24355708

Citation

Synofzik, Matthis, et al. "PNPLA6 Mutations Cause Boucher-Neuhauser and Gordon Holmes Syndromes as Part of a Broad Neurodegenerative Spectrum." Brain : a Journal of Neurology, vol. 137, no. Pt 1, 2014, pp. 69-77.
Synofzik M, Gonzalez MA, Lourenco CM, et al. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014;137(Pt 1):69-77.
Synofzik, M., Gonzalez, M. A., Lourenco, C. M., Coutelier, M., Haack, T. B., Rebelo, A., Hannequin, D., Strom, T. M., Prokisch, H., Kernstock, C., Durr, A., Schöls, L., Lima-Martínez, M. M., Farooq, A., Schüle, R., Stevanin, G., Marques, W., & Züchner, S. (2014). PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain : a Journal of Neurology, 137(Pt 1), 69-77. https://doi.org/10.1093/brain/awt326
Synofzik M, et al. PNPLA6 Mutations Cause Boucher-Neuhauser and Gordon Holmes Syndromes as Part of a Broad Neurodegenerative Spectrum. Brain. 2014;137(Pt 1):69-77. PubMed PMID: 24355708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PNPLA6 mutations cause Boucher-Neuhauser 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,Jr AU - Züchner,Stephan, Y1 - 2013/12/19/ PY - 2013/12/21/entrez PY - 2013/12/21/pubmed PY - 2014/3/13/medline 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 SP - 69 EP - 77 JF - Brain : a journal of neurology JO - Brain VL - 137 IS - Pt 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. SN - 1460-2156 UR - https://wwww.unboundmedicine.com/medline/citation/24355708/PNPLA6_mutations_cause_Boucher_Neuhauser_and_Gordon_Holmes_syndromes_as_part_of_a_broad_neurodegenerative_spectrum_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awt326 DB - PRIME DP - Unbound Medicine ER -