Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor
Por:
Hor, H, Francescatto, L, Bartesaghi, L, Ortega-Cubero, S, Kousi, M, Lorenzo-Betancor, O, Jimenez-Jimenez, FJ, Gironell, A, Clarimon, J, Drechsel, O, Agundez, JAG, Broz, DK, Chiquet-Ehrismann, R, Lleo, A, Coria, F, Garcia-Martin, E, Alonso-Navarro, H, Marti, MJ, Kulisevsky, J, Hor, CN, Ossowski, S, Chrast, R, Katsanis, N, Pastor, P, Estivill, X
Publicada:
15 oct 2015
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 knockout mouse displaying an ET 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.
Filiaciones:
Hor, H:
CRG, Bioinformat & Genom Program, Barcelona, Spain
UPF, Barcelona, Spain
Hosp Mar Med Res Inst IMIM, Barcelona, Spain
CRG CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08003, Catalonia, Spain
Francescatto, L:
Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27710 USA
Bartesaghi, L:
Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland
Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden
CIBERNED, Pamplona 31008, Navarra, Spain
Ortega-Cubero, S:
Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden
Univ Navarra, Sch Med, Ctr Appl Med Res CIMA, Div Neurosci,Neurogenet Lab, Pamplona 31008, Navarra, Spain
Kousi, M:
Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC 27710 USA
Univ Navarra, Sch Med, Clin Univ Navarra, Dept Neurol, Pamplona 31008, Navarra, Spain
Lorenzo-Betancor, O:
Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden
Univ Navarra, Sch Med, Ctr Appl Med Res CIMA, Div Neurosci,Neurogenet Lab, Pamplona 31008, Navarra, Spain
Univ Navarra, Sch Med, Clin Univ Navarra, Dept Neurol, Pamplona 31008, Navarra, Spain
CIBERNED, Pamplona 31008, Navarra, Spain
Jimenez-Jimenez, FJ:
Hosp Univ Sureste, Neurol Sect, Madrid 28030, Spain
Gironell, A:
Hosp Santa Creu & Sant Pau, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
St Pau Biomed Res Inst, Barcelona, Spain
Clarimon, J:
St Pau Biomed Res Inst, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona 08026, Catalonia, Spain
CIBERNED, Barcelona 08026, Catalonia, Spain
Drechsel, O:
CRG, Bioinformat & Genom Program, Barcelona, Spain
UPF, Barcelona, Spain
Agundez, JAG:
Univ Extremadura, Dept Pharmacol, Caceres 10071, Spain
Broz, DK:
Novartis Res Fdn, Friedrich Miescher Inst Biomed Res, Fac Sci, CH-4058 Basel, Switzerland
Novartis Res Fdn, Friedrich Miescher Inst Biomed Res, Dept Biomed, CH-4058 Basel, Switzerland
Univ Basel, CH-4058 Basel, Switzerland
Chiquet-Ehrismann, R:
Novartis Res Fdn, Friedrich Miescher Inst Biomed Res, Fac Sci, CH-4058 Basel, Switzerland
Novartis Res Fdn, Friedrich Miescher Inst Biomed Res, Dept Biomed, CH-4058 Basel, Switzerland
Univ Basel, CH-4058 Basel, Switzerland
Lleo, A:
St Pau Biomed Res Inst, Barcelona, Spain
Coria, F:
Son Espases Univ Hosp, Serv Neurol, Clin Nervous Disorders, Palma De Mallorca 07120, Spain
Garcia-Martin, E:
Univ Extremadura, Dept Biochem & Mol Biol, Caceres 10071, Spain
CIBERNED, Hosp Clin, Neurol Serv, Movement Disorders Unit, Barcelona 08036, Catalonia, Spain
Marti, MJ:
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona 08036, Catalonia, Spain
Kulisevsky, J:
Hosp Santa Creu & Sant Pau, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona 08026, Catalonia, Spain
CIBERNED, Barcelona 08026, Catalonia, Spain
Hor, CN:
CRG, Bioinformat & Genom Program, Barcelona, Spain
UPF, Barcelona, Spain
Hosp Mar Med Res Inst IMIM, Barcelona, Spain
CRG CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08003, Catalonia, Spain
Ossowski, S:
CRG, Bioinformat & Genom Program, Barcelona, Spain
UPF, Barcelona, Spain
Chrast, R:
Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland
Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden
Pastor, P:
UPF, Barcelona, Spain
Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden
Univ Navarra, Sch Med, Ctr Appl Med Res CIMA, Div Neurosci,Neurogenet Lab, Pamplona 31008, Navarra, Spain
Univ Navarra, Sch Med, Clin Univ Navarra, Dept Neurol, Pamplona 31008, Navarra, Spain
CIBERNED, Pamplona 31008, Navarra, Spain
Estivill, X:
CRG, Bioinformat & Genom Program, Barcelona, Spain
Hosp Mar Med Res Inst IMIM, Barcelona, Spain
CRG CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08003, Catalonia, Spain
Univ Hosp Quiron Dexeus, Dexeus Womens Hlth, Barcelona 08028, Catalonia, Spain
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