ArticleNeurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology2023
Han family with essential tremor caused by the P421L variant of the TENM4 gene in China.
Article in Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 4 citations in OpenAlex.
- Transcript Imbalance from TENM4 Exon Skipping: Effects on Epilepsy and Genetic Pleiotropy.Molecular neurobiology · 2025Article
- Six Myths and Misconceptions about Essential Tremor.Tremor and other hyperkinetic movements (New York, N.Y.) · 2024Review
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12 authors at 2 institutions in 1 country.
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Abstract
backgroundEssential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET.
methodsA proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis.
resultsIn a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination.
conclusionThis study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.
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