PUBLICAÇÕES científicas

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

Hor H(1), Francescatto L(2), Bartesaghi L(3), Ortega-Cubero S(4), Kousi M(2), Lorenzo-Betancor O(4), Jiménez-Jiménez FJ(5), Gironell A(6), Clarimón J(7), Drechsel O(8), Agúndez JA(9), Broz DK(10), Chiquet-Ehrismann R(10), Lleó A(11), Coria F(12), García-Martin E(13), Alonso-Navarro H(5), Martí MJ(14), Kulisevsky J(15), Hor CN(16), Ossowski S(8), Chrast R(3), Katsanis N(2), Pastor P(4), Estivill X(17).

(1) Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG) Universitat Pompeu Fabra (UPF) Hospital del Mar Medical Research Institute (IMIM) CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, 08003, Spain hyun.hor@crg.cat.
(2) Center for Human Disease Modeling, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
(3) Department of Medical Genetics, University of Lausanne, Lausanne, 1005, Switzerland Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 171 77, Sweden.
4Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), and Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Navarra, 31008, Spain.
(5)Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, 28030, Spain.
(6) Movement Disorders Unit, Neurology Department, Hospital de Sant Pau Sant Pau Biomedical Research Institute.
(7) Sant Pau Biomedical Research Institute Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia, 08026, Spain.
(8) Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG) Universitat Pompeu Fabra (UPF).
(9) Department of Pharmacology, University of Extremadura, Cáceres, 10071, Spain.
(10) Friedrich Miescher Institute of Biomedical Research, Novartis Research Foundation and University of Basel, Faculty of Sciences and Department of Biomedicine, Basel, 4058, Switzerland.
(11) Sant Pau Biomedical Research Institute.
(12) Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca, 07120, Spain.
(13) Department of Biochemistry and Molecular Biology, University of Extremadura, Cáceres, 10071, Spain.
(14) Movement Disorders Unit, Neurology Service, Hospital Clinic, CIBERNED and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, 08036, Spain.
(15) Movement Disorders Unit, Neurology Department, Hospital de Sant Pau Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia, 08026, Spain.
(16) Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG) Universitat Pompeu Fabra (UPF) Hospital del Mar Medical Research Institute (IMIM) CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, 08003, Spain.
(17) Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG) Universitat Pompeu Fabra (UPF) Hospital del Mar Medical Research Institute (IMIM) CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, 08003, Spain Dexeus Women's Health, University Hospital Quiron-Dexeus, Barcelona, Catalonia, 08028, Spain.

Revisão:Human Molecular Genetics

Data: 17/Jul/2015

Neurologia [ES]

RESUMEN

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole exome sequencing and targeted resequencing in three ET families.

In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families.

Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knock-out mouse displaying an essential tremor phenotype, implicates TENM4 in ET.

Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

CITAÇÃO DO ARTIGO  Hum Mol Genet. 2015 Jul 17. pii: ddv281.

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