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

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.

Teneurin transmembrane protein 4 is not a cause for essential tremor in a Canadian population.

INTRODUCTION: Mutations in teneurin transmembrane protein 4 were reported to be a risk factor for essential tremor, but the relevance of this across different population remains to be examined. The aim of this study was to determine the frequency and spectrum of variations in teneurin transmembrane protein 4 in a cohort of Canadian essential tremor cases. METHODS: The coding portion of teneurin transmembrane protein 4 was sequenced in 269 unrelated essential tremor cases and 288 matched control individuals using a targeted and high-throughput sequencing approach. RESULTS: A total of 157 single nucleotide variations were identified, and from these 99 were a missense or nonsense mutation. A total of 68 cases were carriers of ≥1 rare missense or nonsense mutations, and 39 control individuals were carriers of the same types of variations. Gene-based association tests were used to jointly analyze the single nucleotide variations. CONCLUSIONS: Our results do not support a positive association between teneurin transmembrane protein 4 and the Canadian population. © 2017 International Parkinson and Movement Disorder Society.

Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy.

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells' migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4's role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA.

Rare variant analysis of essential tremor-associated genes in early-onset Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET-associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET-associated genes and PD, in a relatively large Chinese population cohort. METHODS: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT-O) to explore the variant burden of 33 ET-associated genes, using whole-exome sequencing (WES) data from 1494 early-onset PD (EOPD) patients and 1357 control subjects from mainland China. RESULTS: We report that rare loss-of-function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET-related genes were significantly associated with EOPD. INTERPRETATION: This is the first systematic analysis of ET-associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD.

Identification of TENM4 as a Novel Cancer Stem Cell-Associated Molecule and Potential Target in Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is insensitive to endocrine and Her2-directed therapies, making the development of TNBC-targeted therapies an unmet medical need. Since patients with TNBC frequently show a quicker relapse and metastatic progression compared to other breast cancer subtypes, we hypothesized that cancer stem cells (CSC) could have a role in TNBC. To identify putative TNBC CSC-associated targets, we compared the gene expression profiles of CSC-enriched tumorspheres and their parental cells grown as monolayer. Among the up-regulated genes coding for cell membrane-associated proteins, we selected Teneurin 4 (TENM4), involved in cell differentiation and deregulated in tumors of different histotypes, as the object for this study. Meta-analysis of breast cancer datasets shows that TENM4 mRNA is up-regulated in invasive carcinoma specimens compared to normal breast and that high expression of TENM4 correlates with a shorter relapse-free survival in TNBC patients. TENM4 silencing in mammary cancer cells significantly impaired tumorsphere-forming ability, migratory capacity and Focal Adhesion Kinase (FAK) phosphorylation. Moreover, we found higher levels of TENM4 in plasma from tumor-bearing mice and TNBC patients compared to the healthy controls. Overall, our results indicate that TENM4 may act as a novel biomarker and target for the treatment of TNBC.

Parkinson's Disease in Teneurin Transmembrane Protein 4 (TENM4) Mutation Carriers.

INTRODUCTION: Mutations in the teneurin transmembrane protein 4 (TENM4) gene, known to be involved in neuropsychiatric disorders, have been identified in three pedigree of essential tremor (ET) from Spain. ET has overlapping clinical manifestations and epidemiological symptoms with Parkinson's disease (PD), suggesting these two disorders may reflect common genetic risk factors. In this study, we investigated clinical and genetic manifestations in four unrelated pedigrees with both ET and PD in which TENM4 variants were identified. METHODS: We subsequently explored whether TENM4 variants contributed to the risk of developing PD. The frequency of TENM4 variants was evaluated from four PD pedigrees and other 407 subjects. RESULTS: The results revealed 12 different novel heterozygous variants, all at low frequency. A clear general enrichment of TENM4 variants was detected in early onset PD patients (p < 0.001, OR = 5.264, 95% CI = 1.957-14.158). CONCLUSION: The results indicate that rare TENM4 variants may be associated with an increased risk of PD.

Genetic testing of FUS, HTRA2, and TENM4 genes in Chinese patients with essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most prevalent movement disorders. The genetic etiology of ET has not been well defined although a significant proportion (≥50%) are familial cases. Linkage analysis and genome-wide association studies (GWASs) have identified several risk variants. In recent years, whole-exome sequencing of ET has revealed several specific causal variants in FUS (p.Q290X), HTRA2 (p.G399S), and TENM4 (c.4324 G>A, c.4100C>A, and c.3412G>A) genes. OBJECTIVE: To investigate the genetic contribution of these three genes to ET, the protein-coding sequences of FUS, HTRA2, and TENM4 were analyzed in a total of 238 ET patients and 272 controls from eastern China using direct Sanger sequencing. RESULTS: We identified two synonymous coding single nucleotide polymorphisms (SNPs), rs741810 and rs1052352 in FUS, and three previously reported synonymous SNPs, rs11237621, rs689369, and rs2277277 in TENM4. No nonsynonymous exonic variants were identified in these subjects. We found that the frequency of the rs1052352C allele was significantly higher (P = .001) in the ET group than in the control group. CONCLUSION: Overall, our findings suggest that rs1052352 of FUS might contribute to ET risk in Chinese population.

Circular RNA Expression Profiling Identifies Glaucoma-Related Circular RNAs in Various Chronic Ocular Hypertension Rat Models.

Circular RNAs are characterized as a class of covalently closed circular RNA transcripts and are associated with a variety of cellular processes and neurological diseases by sponging microRNAs. Expression profiling of circular RNAs in glaucoma, which is a form of optic neuropathy, has not been performed to date. The most common characteristic of all forms of glaucoma is the loss of retinal ganglion cells. While the pathogenesis of glaucoma is not fully understood, intraocular pressure is unquestionably the only proven modifiable factor which makes chronic ocular hypertension (COH) animals the classical glaucoma models. Based on these findings, we completed the first in-depth study of rat retinal circular RNA expression profiling to identify probable biomarkers for the diagnosis of glaucoma. Two ocular hypertension models were induced by episcleral vein ligation (EVL) and microbead injection in rats. Overall, 15,819 circular RNA were detected. Furthermore, 3,502 differentially expressed circular RNAs verified in both COH rats were identified, of which 691 were upregulated and 2,811 were downregulated. Seven significantly downregulated (both log2FoldChange < -2.5 and adjusted P < 0.001) and seven significantly upregulated (both log2FoldChange > 2.5 and adjusted P < 0.001) circular RNAs were shown. Six target microRNAs aligned with the top 14 circular RNAs were identified. According to the construction of the circular RNA-microRNA network and circBase information, only RNO_CIRCpedia_1775 had the homologous hsa_circ_0023826 in the human genome. The hsa_circ_0023826 and mRNA of the host gene TENM4 (teneurin transmembrane protein 4) were validated in aqueous humor samples of five glaucoma patients and five cataract control patients. The expression of hsa_circ_0023826 showed a significant decrease in glaucoma patients, while TENM4 mRNA showed no significant difference compared to cataract patients (P = 0.024 and P = 0.294, respectively). The results of this study comprehensively characterized the expression profiles of circular RNA in glaucoma-affected eyes, as verified by two different ocular hypertension rat models. Together with the target microRNAs underlying the top differentially expressed circular RNAs, a new target of hsa_circ_0023826 and its host gene TENM4 were identified and further verified in the aqueous humor of glaucoma patients, indicating a promising biomarker for the disease.