NALCN Gene: Sodium Leak Channel, Non-Selective
Essential regulator of neuronal resting membrane potential and rhythmic behavior; mutations cause CLIFAHDD and IHPRF syndromes.
Gene Information Card
| Symbol | NALCN |
|---|---|
| Full Name | sodium leak channel, non-selective |
| Gene Type | protein coding |
| Chromosomal Location | 13q33.1 |
| NCBI Gene ID | 259232 ncbi.nlm.nih.gov/gene/259232 |
| Ensembl ID | ENSG00000102452 |
| UniProt ID | Q8IZF0 |
| OMIM ID | 611549 |
| HGNC ID | 23282 |
| Aliases | FLJ22169, IHPRF1, CLIFAHDD |
Description
The NALCN gene encodes the sodium leak channel, non-selective (NALCN), a voltage-independent, non-selective cation channel that is primarily expressed in neurons. It mediates a background sodium leak current that depolarizes the resting membrane potential, thereby regulating neuronal excitability, pacemaking, and rhythmic behaviors such as respiration and locomotion. NALCN forms a complex with auxiliary subunits (UNC79, UNC80, and NLF-1) and is modulated by G-protein-coupled receptors. Mutations in NALCN cause neurodevelopmental disorders including congenital contractures of limbs and face, hypotonia, and developmental delay (CLIFAHDD) and infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Congenital contractures of limbs and face, hypotonia, and developmental delay (CLIFAHDD) | Missense mutations in the pore-forming region or voltage-sensing domain lead to gain-of-function or altered channel gating, disrupting neuronal excitability. | OMIM #616266; ClinVar submissions |
| Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) | Loss-of-function mutations (nonsense, frameshift, splice-site) result in haploinsufficiency or non-functional channels, impairing resting membrane potential maintenance. | OMIM #615419; ClinVar submissions |
| NALCN-related neurodevelopmental disorder with intellectual disability | Various missense and truncating mutations cause a spectrum of phenotypes including intellectual disability, seizures, and movement disorders. | ClinVar; literature (e.g., Chong et al., 2015) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.4 | Medium |
| Adrenal gland | 8.9 | Low |
| Testis | 6.2 | Low |
| Heart | 2.1 | Not detected |
| Liver | 0.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.3 | High expression; used in neuronal studies |
| SK-N-AS (neuroblastoma) | 12.8 | Moderate expression |
| U-87 MG (glioblastoma) | 8.5 | Low expression |
| HEK293 (embryonic kidney) | 0.2 | Not expressed; often used for heterologous expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1982T>C (p.Leu661Pro) | Missense | Rare (found in CLIFAHDD) | Gain-of-function; alters channel gating |
| c.3160C>T (p.Arg1054Ter) | Nonsense | Rare (found in IHPRF) | Loss-of-function; premature truncation |
| c.2677G>A (p.Gly893Arg) | Missense | Rare (found in CLIFAHDD) | Gain-of-function; altered voltage sensitivity |
| c.1234delC (p.Leu412TrpfsTer19) | Frameshift | Rare (found in IHPRF) | Loss-of-function; haploinsufficiency |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and splice-site mutations that reduce NALCN protein levels or channel activity, leading to IHPRF syndrome.
Gain of Function (GOF)
Missense mutations that increase channel conductance or alter gating, leading to CLIFAHDD syndrome.
Dominant Negative (DN)
Not well established; some missense mutations may exert dominant-negative effects by disrupting channel complex assembly, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • voltage-gated sodium channel activity | • monoatomic ion channel activity |
| • sodium ion transmembrane transport | • regulation of membrane potential |
| • neuronal action potential | • response to calcium ion |
Pathways
• Sodium leak channel pathway (NALCN/UNC79/UNC80)
• G-protein coupled receptor signaling (modulation of NALCN)
• Regulation of neuronal resting membrane potential
Protein Summary
The NALCN protein is a 1,738-amino-acid, multi-pass membrane protein with four homologous domains (I-IV), each containing six transmembrane segments (S1-S6). It lacks a voltage sensor in S4, consistent with its voltage-independent gating. The channel is constitutively active and selective for sodium over potassium, with a small permeability to calcium. It forms a complex with UNC79, UNC80, and NLF-1, which are essential for its surface expression and function. NALCN is regulated by G-protein-coupled receptors (e.g., substance P, neurotensin) and is critical for neuronal pacemaking, respiratory rhythm, and circadian behavior.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NALCN Knockout HEK293 Cell Line | EDJ-KQ14367 | Human | 259232 | Details Get a Quote |
| NALCN Knockout A-549 Cell Line | EDJ-KQ44505 | Human | 259232 | Details Get a Quote |
| NALCN Knockout HeLa Cell Line | EDJ-KQ44506 | Human | 259232 | Details Get a Quote |
| NALCN Knockout HCT 116 Cell Line | EDJ-KQ76179 | Human | 259232 | Details Get a Quote |
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