Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

Matias Wagner, Jonathan Lévy, Sabine Jung-Klawitter, Somayeh Bakhtiari, Fabiola Monteiro, Reza Maroofian, Tatjana Bierhals, Maja Hempel, Monique Elmaleh-Bergès, Joao P. Kitajima, Chong A. Kim, Julia G. Salomao, David J. Amor, Monica S. Cooper, Laurence Perrin, Eva Pipiras, Axel Neu, Mohammad Doosti, Ehsan G. Karimiani, Mehran B. ToosiHenry Houlden, Sheng Chih Jin, Yue C. Si, Lance H. Rodan, Hanka Venselaar, Michael C. Kruer, Fernando Kok, Georg F. Hoffmann, Tim M. Strom, Saskia B. Wortmann, Anne Claude Tabet, Thomas Opladen

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Purpose: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

Original languageEnglish
Pages (from-to)1061-1068
Number of pages8
JournalGenetics in Medicine
Issue number6
StatePublished - Jun 1 2020


  • TNR
  • cerebral palsy
  • developmental disorder
  • exome sequencing
  • spastic tetraparesis


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