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

Hyun Hor, Ludmila Francescatto, Luca Bartesaghi, Sara Ortega-Cubero, Maria Kousi, Oswaldo Lorenzo-Betancor, Felix J. Jiménez-Jiménez, Alexandre Gironell, Jordi Clarimón, Oliver Drechse, José A.G. Agúndez, Daniela Kenzelmann Broz, Ruth Chiquet-Ehrismann, Alberto Lleó, Francisco Coria, Elena García-Martin, Hortensia Alonso-Navarro, Maria J. Martí, Jaume Kulisevsky, Charlotte N. Hor & 5 others Stephan Ossowski, Roman Chrast, Nicholas Katsanis, Pau Pastor, Xavier P. Estivill

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Essential tremor (ET) is acommonmovement 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.

Original languageEnglish
Pages (from-to)5677-5686
Number of pages10
JournalHuman Molecular Genetics
Volume24
Issue number20
DOIs
Publication statusPublished - 5 Jun 2015
Externally publishedYes

Fingerprint

Essential Tremor
Missense Mutation
Exome
Oligodendroglia
Zebrafish
Mutation
Inborn Genetic Diseases
Mutant Proteins
Axon Guidance
Knockout Mice
Embryonic Structures
Central Nervous System
Alleles
Phenotype
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hor, H., Francescatto, L., Bartesaghi, L., Ortega-Cubero, S., Kousi, M., Lorenzo-Betancor, O., ... Estivill, X. P. (2015). Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Human Molecular Genetics, 24(20), 5677-5686. https://doi.org/10.1093/hmg/ddv281

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. / Hor, Hyun; Francescatto, Ludmila; Bartesaghi, Luca; Ortega-Cubero, Sara; Kousi, Maria; Lorenzo-Betancor, Oswaldo; Jiménez-Jiménez, Felix J.; Gironell, Alexandre; Clarimón, Jordi; Drechse, Oliver; Agúndez, José A.G.; Kenzelmann Broz, Daniela; Chiquet-Ehrismann, Ruth; Lleó, Alberto; Coria, Francisco; García-Martin, Elena; Alonso-Navarro, Hortensia; Martí, Maria J.; Kulisevsky, Jaume; Hor, Charlotte N.; Ossowski, Stephan; Chrast, Roman; Katsanis, Nicholas; Pastor, Pau; Estivill, Xavier P.

In: Human Molecular Genetics, Vol. 24, No. 20, 05.06.2015, p. 5677-5686.

Research output: Contribution to journalArticle

Hor, H, Francescatto, L, Bartesaghi, L, Ortega-Cubero, S, Kousi, M, Lorenzo-Betancor, O, Jiménez-Jiménez, FJ, Gironell, A, Clarimón, J, Drechse, O, Agúndez, JAG, Kenzelmann Broz, D, Chiquet-Ehrismann, R, Lleó, A, Coria, F, García-Martin, E, Alonso-Navarro, H, Martí, MJ, Kulisevsky, J, Hor, CN, Ossowski, S, Chrast, R, Katsanis, N, Pastor, P & Estivill, XP 2015, 'Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor', Human Molecular Genetics, vol. 24, no. 20, pp. 5677-5686. https://doi.org/10.1093/hmg/ddv281
Hor H, Francescatto L, Bartesaghi L, Ortega-Cubero S, Kousi M, Lorenzo-Betancor O et al. Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Human Molecular Genetics. 2015 Jun 5;24(20):5677-5686. https://doi.org/10.1093/hmg/ddv281
Hor, Hyun ; Francescatto, Ludmila ; Bartesaghi, Luca ; Ortega-Cubero, Sara ; Kousi, Maria ; Lorenzo-Betancor, Oswaldo ; Jiménez-Jiménez, Felix J. ; Gironell, Alexandre ; Clarimón, Jordi ; Drechse, Oliver ; Agúndez, José A.G. ; Kenzelmann Broz, Daniela ; Chiquet-Ehrismann, Ruth ; Lleó, Alberto ; Coria, Francisco ; García-Martin, Elena ; Alonso-Navarro, Hortensia ; Martí, Maria J. ; Kulisevsky, Jaume ; Hor, Charlotte N. ; Ossowski, Stephan ; Chrast, Roman ; Katsanis, Nicholas ; Pastor, Pau ; Estivill, Xavier P. / Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 20. pp. 5677-5686.
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abstract = "Essential tremor (ET) is acommonmovement 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.",
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T1 - Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

AU - Hor, Hyun

AU - Francescatto, Ludmila

AU - Bartesaghi, Luca

AU - Ortega-Cubero, Sara

AU - Kousi, Maria

AU - Lorenzo-Betancor, Oswaldo

AU - Jiménez-Jiménez, Felix J.

AU - Gironell, Alexandre

AU - Clarimón, Jordi

AU - Drechse, Oliver

AU - Agúndez, José A.G.

AU - Kenzelmann Broz, Daniela

AU - Chiquet-Ehrismann, Ruth

AU - Lleó, Alberto

AU - Coria, Francisco

AU - García-Martin, Elena

AU - Alonso-Navarro, Hortensia

AU - Martí, Maria J.

AU - Kulisevsky, Jaume

AU - Hor, Charlotte N.

AU - Ossowski, Stephan

AU - Chrast, Roman

AU - Katsanis, Nicholas

AU - Pastor, Pau

AU - Estivill, Xavier P.

PY - 2015/6/5

Y1 - 2015/6/5

N2 - Essential tremor (ET) is acommonmovement 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.

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