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Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity

Journal of Human Genetics volume 71, pages 231–237 (2026)Cite this article

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Abstract

Tenascin-R (TNR) is an extracellular matrix glycoprotein that is essential for the formation of perineuronal nets in the central nervous system and is critical for neurite outgrowth, synaptic plasticity, and neural stem cell proliferation and differentiation. Biallelic TNR variants were reported to cause neurodevelopmental disorders with developmental delay, hypotonia, spasticity, and a variety of motor abnormalities. Here, we describe two Japanese siblings sharing novel compound heterozygous TNR missense variants (NM_003285.3:c.[1783 G > A];[3766 C > T] p.[(Asp595Asn)];[(Arg1256Cys)]) identified by exome and Sanger sequencing. The elder brother had dystonia, while the younger sister was asymptomatic except for adult-onset restless legs syndrome. Their development and intellect were normal. A total of 15 patients, including 13 previously reported patients, showed diverse phenotypic variability and severity, even among individuals sharing the same variants, indicating variable expressivity and reduced penetrance possibly influenced by genetic or environmental modifiers. Our findings extend the clinical spectrum of TNR-related disease and highlight the need for further accumulation of clinical cases and functional studies to understand genotype–phenotype correlations and the pathogenesis of diseases.

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The relevant genomic data have not been deposited to public databases but are available on request to the corresponding author.

References

  1. di Biase L, Di Santo A, Caminiti ML, Pecoraro PM, Carbone SP, Di Lazzaro V. Dystonia diagnosis: clinical neurophysiology and genetics. J Clin Med. 2022;11:4184.

  2. Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D, Gabbert C, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force - An update. Mov Disord. 2022;37:905–35.

    Article  PubMed  Google Scholar 

  3. Thomsen M, Lange LM, Zech M, Lohmann K. Genetics and pathogenesis of dystonia. Annu Rev Pathol. 2024;19:99–131.

    Article  CAS  PubMed  Google Scholar 

  4. Galtrey CM, Fawcett JW. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev. 2007;54:1–18.

    Article  CAS  PubMed  Google Scholar 

  5. Pesheva P, Spiess E, Schachner M. J1-160 and J1-180 are oligodendrocyte-secreted nonpermissive substrates for cell adhesion. J Cell Biol. 1989;109:1765–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bruckner G, Grosche J, Schmidt S, Hartig W, Margolis RU, Delpech B, et al. Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J Comp Neurol. 2000;428:616–29.

    Article  CAS  PubMed  Google Scholar 

  7. Bukalo O, Schachner M, Dityatev A. Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience. 2001;104:359–69.

    Article  CAS  PubMed  Google Scholar 

  8. Xu JC, Xiao MF, Jakovcevski I, Sivukhina E, Hargus G, Cui YF, et al. The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice. J Cell Sci. 2014;127:641–52.

    CAS  PubMed  Google Scholar 

  9. Montag-Sallaz M, Montag D. Severe cognitive and motor coordination deficits in tenascin-R-deficient mice. Genes Brain Behav. 2003;2:20–31.

    Article  CAS  PubMed  Google Scholar 

  10. Christen M, Gutierrez-Quintana R, James M, Faller KME, Lowrie M, Rusbridge C, et al. A TNR frameshift variant in Weimaraner dogs with an exercise-induced paroxysmal movement disorder. Mov Disord. 2023;38:1094–99.

    Article  CAS  PubMed  Google Scholar 

  11. Sethi MK, Zaia J. Extracellular matrix proteomics in schizophrenia and Alzheimer’s disease. Anal Bioanal Chem. 2017;409:379–94.

    Article  CAS  PubMed  Google Scholar 

  12. Dong Y, Zhao K, Qin X, Du G, Gao L. The mechanisms of perineuronal net abnormalities in contributing aging and neurological diseases. Ageing Res Rev. 2023;92:102092.

    Article  CAS  PubMed  Google Scholar 

  13. Wagner M, Levy J, Jung-Klawitter S, Bakhtiari S, Monteiro F, Maroofian R, et al. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus. Genet Med. 2020;22:1061–68.

    Article  CAS  PubMed  Google Scholar 

  14. Utsuno Y, Hamada K, Hamanaka K, Miyoshi K, Tsuchimoto K, Sunada S, et al. Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders. J Hum Genet. 2024;69:69–77.

    Article  CAS  PubMed  Google Scholar 

  15. Sinha A, Kawakami J, Cole KS, Ladutska A, Nguyen MY, Zalmai MS, et al. Protein-protein interactions between tenascin-R and RPTPζ/phosphacan are critical to maintain the architecture of perineuronal nets. J Biol Chem. 2023;299:104952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature. 2024;630:493–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guerois R, Nielsen JE, Serrano L. Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol. 2002;320:369–87.

    Article  CAS  PubMed  Google Scholar 

  18. Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L. The FoldX web server: an online force field. Nucleic Acids Res. 2005;33:W382–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramos VF, Karp BI, Hallett M. Tricks in dystonia: ordering the complexity. J Neurol Neurosurg Psychiatry. 2014;85:987–93.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Carnemolla B, Leprini A, Borsi L, Querze G, Urbini S, Zardi L. Human tenascin-R. Complete primary structure, pre-mRNA alternative splicing and gene localization on chromosome 1q23-q24. J Biol Chem. 1996;271:8157–60.

    Article  CAS  PubMed  Google Scholar 

  21. Michetti C, Falace A, Benfenati F, Fassio A. Synaptic genes and neurodevelopmental disorders: From molecular mechanisms to developmental strategies of behavioral testing. Neurobiol Dis. 2022;173:105856.

    Article  CAS  PubMed  Google Scholar 

  22. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 1990;13:281–5.

    Article  CAS  PubMed  Google Scholar 

  23. Simonyan K, Cho H, Hamzehei Sichani A, Rubien-Thomas E, Hallett M. The direct basal ganglia pathway is hyperfunctional in focal dystonia. Brain. 2017;140:3179–90.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Earley CJ, Hyland K, Allen RP. Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med. 2006;7:263–8.

    Article  PubMed  Google Scholar 

  25. Allen RP. Restless Leg Syndrome/Willis-Ekbom Disease Pathophysiology. Sleep Med Clin. 2015;10:207–14.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Morawski M, Dityatev A, Hartlage-Rübsamen M, Blosa M, Holzer M, Flach K, et al. Tenascin-R promotes assembly of the extracellular matrix of perineuronal nets via clustering of aggrecan. Philos Trans R Soc Lond B Biol Sci. 2014;369:20140046.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gwilt MA, Hodgson AR, Axelsson SFA, Cockcroft GJ, McIver LB, Hird M, et al. Hippocampal perineuronal net degradation identifies prefrontal and striatal circuits involved in schizophrenia-like changes in marmosets. Sci Adv. 2025;11:eadu0975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet. 1997;17:40–8.

    Article  CAS  PubMed  Google Scholar 

  29. Carecchio M, Invernizzi F, Gonzàlez-Latapi P, Panteghini C, Zorzi G, Romito L, et al. Frequency and phenotypic spectrum of KMT2B dystonia in childhood: a single-center cohort study. Mov Disord. 2019;34:1516–27.

    Article  CAS  PubMed  Google Scholar 

  30. Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, et al. Mutations in INPP5K, encoding a phosphoinositide 5-phosphatase, cause congenital muscular dystrophy with cataracts and mild cognitive impairment. Am J Hum Genet. 2017;100:523–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yousaf S, Sheikh SA, Riazuddin S, Waryah AM, Ahmed ZM. INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family. Clin Genet. 2018;93:682–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the individuals and their family for their participation in this study. We also thank N. Watanabe, T. Miyama, M. Sato, S. Sugimoto, and K. Takabe for their technical assistance. We thank Edanz (https://jp.edanz.com/ac) for editing the English text of a draft of this manuscript. This work was supported by the Japan Agency for Medical Research and Development (AMED) (grant numbers JP25ek0109674, JP25ek0109760, JP25ek0109617, JP25ek0109648, and JP25ek0109677 to N. Matsumoto); the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (grant number JP22K15901 to A. Fujita, JP23H02829 to S. Miyatake, JP23H02877 to T. Mizuguchi, JP22K15901 to K. Hamanaka, JP23K07229 to Y. Uchiyama, JP23K15353 to N. Tsuchida, JP21K07869 to E. Koshimizu, JP24K18862 to M. Sakamoto, and JP24K02230 to N. Matsumoto); the Takeda Science Foundation (T. Mizuguchi and N. Matsumoto); and Kawano Masanori Memorial Public Interest Incorporated Foundation for the Promotion of Pediatrics (S. Miyatake).

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Atsuhiro Ozaki, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi & Naomichi Matsumoto

  2. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Masamune Sakamoto

  3. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan

    Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama & Naomichi Matsumoto

  4. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Satoko Kumada

  5. Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Keisuke Hamada & Kazuhiro Ogata

  6. Innovation & Research Support Center, Graduate School, International University of Health and Welfare, Tokyo, Japan

    Kazuhiro Ogata

  7. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Jun Ikezawa

  8. Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan

    Satoko Miyatake & Naomichi Matsumoto

  9. Department of Neurogenetics, Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan

    Satoko Miyatake

  10. Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan

    Naomichi Matsumoto

Authors
  1. Atsuhiro Ozaki
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  2. Masamune Sakamoto
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  4. Keisuke Hamada
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  5. Kazuhiro Ogata
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  13. Takeshi Mizuguchi
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Correspondence to Naomichi Matsumoto.

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Ozaki, A., Sakamoto, M., Kumada, S. et al. Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity. J Hum Genet 71, 231–237 (2026). https://doi.org/10.1038/s10038-025-01431-0

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