Alternative titles; symbols
HGNC Approved Gene Symbol: NALF1
Cytogenetic location: 13q33.3 Genomic coordinates (GRCh38): 13:107,163,510-107,867,496 (from NCBI)
NALF1 is a conserved endoplasmic reticulum (ER) protein that regulates the Na+ leak channel NALCN (611549) (Xie et al., 2013).
Xie et al. (2013) cloned C. elegans Nalf1, which they called Nlf1. The C. elegans protein has N-terminal ER retention motifs, a central evolutionarily conserved NLF domain, and a C-terminal transmembrane segment. Nlf1 showed broad, specific expression in C. elegans nervous system and localized to the ER. Structure-function analysis demonstrated that both the N- and C-terminal regions of Nlf1 were required for its ER localization and that ER localization was critical for Nlf1 function. The mouse homolog of Nlf1 also localized to the ER in transfected COS-7 cells. Topology analysis showed that mouse and C. elegans Nlf1 localized to the ER in yeast, with both exhibiting a tail-anchored, type I ER membrane topology.
Gross (2022) mapped the NALF1 gene to chromosome 13q33.3 based on an alignment of the NALF1 sequence (GenBank BC146878) with the genomic sequence (GRCH38).
Using a genetic screen in C. elegans, Xie et al. (2013) identified Nlf1 as a gene in the same genetic pathway as NCA genes. Loss-of-function mutants of Nlf1 produced a similar fainting phenotype as NCA loss-of-function mutants and rescued the coiler phenotype exhibited by NCA gain-of-function mutants. Further analysis of Nlf1 mutant C. elegans indicated that Nlf1 was critically required in premotor interneurons to prevent fainting, as Nlf1 and the NCA channel potentiated premotor interneurons. Nlf1 promoted axonal localization of the NCA channel, thereby contributing to the NCA channel-mediated Na+ leak current that maintains the resting membrane potential, and to the excitability and activity of C. elegans premotor interneurons. The function of Nlf1 was conserved between C. elegans and mouse, as demonstrated by transgenic expression of mouse Nlf1 in C. elegans Nlf1 mutants and by Nlf1 knockdown in primary mouse cortical neuron cultures. Immunoprecipitation analysis revealed that mouse Nlf1 interacted with the Na+ leak channel Nalcn (611549), which is homologous to the C. elegans NCA channel, in cotransfected in COS-7 cells.
Gross, M. B. Personal Communication. Baltimore, Md. 5/26/2022.
Xie, L., Gao, S., Alcaire, S. M., Aoyagi, K., Wang, Y., Griffin, J. K., Stagljar, I., Nagamatsu, S., Zhen, M. NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion. Neuron 77: 1069-1082, 2013. [PubMed: 23522043] [Full Text: https://doi.org/10.1016/j.neuron.2013.01.018]