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. 2023 Jun;44(6):2003-2015.
doi: 10.1007/s10072-023-06603-4. Epub 2023 Jan 23.

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China

Wu Chi #  1   2   3 , Min Wu #  1 , Han-Lu Wang #  1 , Qiu-Yan Wu  1 , Yan-Ping Zhang  1 , Ya-Nan Hu  1 , Yao-Bin Zhu  1   4 , Xin-Fu Lin  1   5 , Ting Chen  6 , Jie-Wei Luo  7   8 , Xing-Lin Ruan  9 , Yun-Fei Li  10   11
Affiliations

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China

Wu Chi et al. Neurol Sci. 2023 Jun.

Abstract

Background: Essential 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.

Methods: A 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.

Results: In 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.

Conclusion: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

Keywords: Essential tremor; Missense variation; Myelin sheath; Oligodendrocyte; TENM4.

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References

    1. Benito-Leon J, Louis ED (2006) Essential tremor: emerging views of a common disorder. Nat Clin Pract Neurol 2(12):666–78. https://doi.org/10.1038/ncpneuro0347 . (quiz 2p following 91) - DOI - PubMed
    1. Tallon-Barranco A, Vazquez A, Javier Jimenez-Jimenez F, Orti-Pareja M, Gasalla T, Cabrera-Valdivia F et al (1997) Clinical features of essential tremor seen in neurology practice: a study of 357 patients. Parkinsonism Relat Disord 3(4):187–190. https://doi.org/10.1016/s1353-8020(97)00031-x - DOI - PubMed
    1. Jimenez-Jimenez FJ, Alonso-Navarro H, Garcia-Martin E, Lorenzo-Betancor O, Pastor P, Agundez JA (2013) Update on genetics of essential tremor. Acta Neurol Scand 128(6):359–371. https://doi.org/10.1111/ane.12148 - DOI - PubMed
    1. Siokas V, Aloizou AM, Tsouris Z, Liampas I, Aslanidou P, Dastamani M et al (2020) Genetic risk factors for essential tremor: a review. Tremor Other Hyperkinet Mov (N Y) 10:4. https://doi.org/10.5334/tohm.67 - DOI - PubMed
    1. Louis ED (2001) Etiology of essential tremor: should we be searching for environmental causes? Mov Disord 16(5):822–829. https://doi.org/10.1002/mds.1183 - DOI - PubMed

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