Alternative titles; symbols
HGNC Approved Gene Symbol: TMEFF1
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38) : 9:100,473,149-100,577,636 (from NCBI)
TMEFF1 is a type I transmembrane protein primarily expressed in neurons (Dai et al., 2024).
Eib and Martens (1996) cloned a novel Xenopus gene, 7365, that is enriched in neuroendocrine tissues. The predicted protein contains a signal peptide, a transmembrane domain, 2 follistatin modules, and an EGF-like domain, a cysteine-rich region first identified in epidermal growth factor (131530). Eib et al. (1998) stated that the unique EGF-like domain and transmembrane and cytoplasmic regions of the human homolog (U19878) are nearly identical to those found in the mouse and frog homologs.
Dai et al. (2024) stated that TMEFF1 is a transmembrane protein that forms a family with TMEFF2 (605734). TMEFF1 is located in the plasma membrane and is expressed constitutively in human and mouse central nervous system (CNS) neurons.
Herpes simplex virus (HSV)-1 is a neurotropic virus that causes herpes simplex encephalitis. Using a knockout screen in SK-N-SH human neuroblastoma cells, Dai et al. (2024) identified TMEFF1 as a neuron-specific restriction factor of HSV-1. Overexpression of mouse Tmeff1 in HEK293T cells was sufficient to restrict HSV-1 infection, and TMEFF1 knockout elevated HSV-1 replication in human neurons, accompanied by a significant level of neuronal cell death. Analysis with Tmeff1 -/- mice demonstrated that Tmeff1 was essential for host defense against HSV-1 brain infection in mice in vivo. Immunoprecipitation and mass spectrometric analyses showed that TMEFF1 interacted with nectin-1 (NECTIN1; 600644), NMHC IIA (MYH9; 160775), and NMHC IIB (MYH10; 160776). The N-terminal extracellular region of TMEFF1 interacted with nectin-1, whereas the C-terminal intracellular region of TMEFF1 interacted with NMHC IIA. By interacting with these proteins, TMEFF1 blocked cellular entry of HSV-1, thereby preventing viral replication in the CNS.
Eib et al. (1998) used somatic cell hybrids and fluorescence in situ hybridization to map the TMEFF1 gene to human chromosome 9q31.
Associations Pending Confirmation
For discussion of a possible association between susceptibility to herpes simplex virus (HSV) encephalitis (see, e.g., IIAE1; 610551) and variation in the TMEFF1 gene, see 603421.0001 and 603421.0002. These 2 homozygous variants in the TMEFF1 gene were identified in 2 unrelated patients from a cohort of 319 individuals with HSV encephalitis (HSE) who underwent whole-exome sequencing.
Dai et al. (2024) found that homozygous knockout of the Tmeff1 gene in mice (Tmeff1-null mice) resulted in lower survival rates following HSV-1 infection compared to wildtype mice. Mouse Tmeff1 was expressed in the brainstem, but not in the eyes or trigeminal ganglia. Consistent with this, HSV-1 was detected in brainstem sections of Tmeff1-null mice infected with HSV-1, but not in the eyes or trigeminal ganglia. In vitro HSV-1 infection of Tmeff1-null neurons, astrocytes, and microglia led to an elevated level of viral replication in neurons but not in astrocytes or microglia. The findings indicated that Tmeff1 is essential for protection of neurons from HSV-1 in an in vivo model of HSE.
This variant is classified as a variant of unknown significance because its contribution to susceptibility to herpes simplex virus (HSV) encephalitis (see, e.g., IIAE1, 610551) has not been confirmed.
In a 19-year-old girl (P1), born of unrelated parents of Algerian and Moroccan descent (kindred A) living in France, with an episode of suspected HSV encephalitis (HSE) at 2.5 years of age, Chan et al. (2024) identified a homozygous c.130C-G transversion in exon 1 of the TMEFF1 gene, resulting in a pro44-to-ala (P44A) substitution at the N terminus of the protein. The variant, which was found by whole-exome sequencing of a cohort of 319 patients with HSE and confirmed by Sanger sequencing, segregated with the disease in the family. Detailed in vitro studies of transfected HEK293 and HeLa cells and patient-derived neuronal iPSCs showed that the P44A variant protein was expressed normally on the cell surface. However, infection of patient P44A neuronal cells with HSV-1 resulted in higher levels of viral replication compared to wildtype, indicating enhanced susceptibility to HSV-1 infection; this defect could be rescued by pretreatment with beta-IFN (147640). In HeLa cells, the P44A protein failed to restrict the early translocation of HSV-1 into the cell nucleus, although it coimmunoprecipitated normally with NECTIN1 (600644). The patient presented at 2.5 years of age with high fever and coma associated with large cortical lesions in the left temporal region. PCR on CSF was negative for HSV, and serologic tests for antibodies against various viruses yielded negative results. A diagnosis of HSE was suspected and she was treated with intravenous acyclovir. She relapsed 3 weeks later, during which anti-HSV-1 antibodies were detected, although PCR on CSF for HSV remained negative. She was treated and discharged, but had severe persistent neurologic sequelae, including epilepsy. She had no other severe infectious diseases or other abnormalities, and family history was unremarkable.
Hamosh (2024) noted that the P44A variant (rs199581308) was present in gnomAD (v4.1.0) in the homozygous state in 2 individuals and in the heterozygous state in 2,975 of 1,543,100 individuals (frequency of 0.0019).
This variant is classified as a variant of unknown significance because its contribution to susceptibility to herpes simplex virus (HSV) encephalitis (see, e.g., IIAE1, 610551) has not been confirmed.
In a 19-year-old boy (P2), born of consanguineous Turkish parents (kindred B), with an episode of suspected HSV encephalitis (HSE) at 5 years of age, Chan et al. (2024) identified a homozygous A-to-G transition in intron 9 (c.1059-2A-G) of the TMEFF1 gene, resulting in a splicing defect at the C terminus. The variant was found by whole-exome sequencing of 319 HSE patients and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for the variant, indicating segregation within the family, but there was a clinically unaffected older brother with the same homozygous variant who had positive serology for HSV-1, which the authors attributed to incomplete penetrance. Three mutant transcripts were produced from the splice site variant: M1 was a 21-bp in-frame deletion (Lys354_Arg360del), M2 was a deletion of exon 10 and an insertion of part of the 3-prime UTR (Lys354_Val380del-3-prime UTRins48Ter), and M3 was a deletion of exons 9 and 10 with the same 3-prime UTR insertion (Cys301_Val380del-3-prime UTRins48Ter). In patient-derived iPSC cortical neurons, the proportions of the variant transcripts were M1 (45%), M2 (45%), and M3 (10%). Detailed in vitro studies of transfected HEK293 and HeLa cells and patient-derived neuronal iPSCs showed that M1 was expressed on the cell membrane, M2 was in both the cell membrane and cytoplasm, and M3 was solely in the cytoplasm. Of note, the M2 protein was larger than wildtype TMEFF1. In vitro infection of patient neuronal cells with HSV-1 resulted in higher levels of viral replication compared to wildtype, indicating enhanced susceptibility to HSV-1 infection; this defect could be rescued by pretreatment with beta-IFN (147640). In HeLa cells, the M3 protein failed to restrict the early translocation of HSV-1 into the cell nucleus, whereas M1 and M2 maintained residual function. M1 coimmunoprecipitated normally with NECTIN1 (600644), M2 was weakly associated with NECTIN1, and M3 did not precipitate with NECTIN1. P2 presented at 5 years of age with seizures associated with large cortical lesions in the temporooccipital regions consistent with HSE, but PCR on CSF was negative and viral serologic tests were not performed. He was treated with intravenous acyclovir and recovered, although he had persistent neurologic sequelae, including epilepsy. He had no other severe infectious diseases or other abnormalities, and family history was unremarkable.
Hamosh (2024) noted that the c.1059-2A-G variant was present in gnomAD (v4.1.0) in heterozygosity only in 25 of 1,605,962 alleles (frequency of 1.6 x 10(-5)).
Chan, Y.-H., Liu, Z., Bastard, P., Khobrekar, N., Hutchison, K. M., Yamazaki, Y., Fan, Q., Matuozzo, D., Harschnitz, O., Kerrouche, N., Nakajima, K., Amin, P., and 37 others. Human TMEFF1 is a restriction factor for herpes simplex virus in the brain. Nature 632: 390-400, 2024. [PubMed: 39048830] [Full Text: https://doi.org/10.1038/s41586-024-07745-x]
Dai, Y., Idorn, M., Serrero, M. C., Pan, X., Thomsen, E. A., Narita, R., Maimaitili, M., Qian, X., Iversen, M. B., Reinert, L. S., Flygaard, R. K., Chen, M., and 17 others. TMEFF1 is a neuron-specific restriction factor for herpes simplex virus. Nature 632: 383-389, 2024. [PubMed: 39048823] [Full Text: https://doi.org/10.1038/s41586-024-07670-z]
Eib, D. W., Martens, G. J. A novel transmembrane protein with epidermal growth factor and follistatin domains expressed in the hypothalamo-hypophysial axis of Xenopus laevis. J. Neurochem. 67: 1047-1055, 1996. [PubMed: 8752111] [Full Text: https://doi.org/10.1046/j.1471-4159.1996.67031047.x]
Eib, D. W., Merkx, G. F. M., Martens, G. J. M., Cremers, F. P. M. Assignment of H7365 (C9orf2) to human chromosome band 9q31 by somatic cell hybrid analysis and fluorescence in situ hybridization. Cytogenet. Cell Genet. 81: 180-181, 1998. [PubMed: 9730596] [Full Text: https://doi.org/10.1159/000015023]
Hamosh, A. Personal Communication. Baltimore, Md. 11/15/2024.