Institute of Human Genetics, Faculty of Medicine, Technical University München, Munich, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
Genet Med. 2020 Jun;22(6):1061-1068. doi: 10.1038/s41436-020-0768-7. Epub 2020 Feb 26.
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.
Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR.
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.
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.
TNR（Tenascin-R）编码一种细胞外基质糖蛋白，参与轴突生长和神经细胞黏附、增殖和迁移、轴突导向、髓鞘形成和突触可塑性。Tenascin-R 仅在中枢神经系统中表达，出生后表达最高。该蛋白对于包绕中间神经元的神经周细胞网络的形成至关重要。然而，Tenascin-R 在人类疾病中的作用在很大程度上尚不清楚。我们旨在将 TNR 确立为人类疾病基因，并阐明其相关的临床表型谱。
使用外显子组测序和在线匹配工具来鉴定 TNR 中存在双等位基因突变的患者。
我们从 8 个无关联的家系中确定了 13 名个体，他们均存在 TNR 的双等位基因突变，表现为痉挛性偏瘫或四肢瘫、脊柱肌张力减退、发育迟缓以及一过性角弓反张。鉴定到 4 种纯合性失活功能突变和 4 种不同的错义突变。
我们将 TNR 确立为一种常染色体隐性非进行性神经发育障碍的疾病基因，其特征为痉挛和一过性角弓反张，并强调了中枢神经系统细胞外基质蛋白在痉挛性疾病发病机制中的作用。
