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Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor
- Source :
- Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid, HUMAN MOLECULAR GENETICS, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, instname, Human Molecular Genetics, vol. 24, no. 20, pp. 5677-5686
- Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- Adult
Male
Essential Tremor
Population
DNA Mutational Analysis
Mutation, Missense
Biology
Dominant-Negative Mutation
medicine.disease_cause
Mice
Young Adult
Genetics
medicine
Missense mutation
Animals
Humans
Exome
education
Molecular Biology
Zebrafish
Genetics (clinical)
Exome sequencing
education.field_of_study
Mutation
Membrane Glycoproteins
General Medicine
Articles
Middle Aged
biology.organism_classification
Phenotype
Axons
3. Good health
Pedigree
Oligodendroglia
Protein Transport
Axon guidance
Female
Subjects
Details
- ISSN :
- 09646906
- Database :
- OpenAIRE
- Journal :
- Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid, HUMAN MOLECULAR GENETICS, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, instname, Human Molecular Genetics, vol. 24, no. 20, pp. 5677-5686
- Accession number :
- edsair.doi.dedup.....1a971459bf3b5e66e1decf6a0dadeadf