CNNM4: Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4
A key regulator of magnesium homeostasis linked to Jalili syndrome and cone-rod dystrophy
Gene Information Card
| Symbol | CNNM4 |
|---|---|
| Full Name | Cyclin and CBS domain divalent metal cation transport mediator 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q11.2 |
| NCBI Gene ID | 26504 ncbi.nlm.nih.gov/gene/26504 |
| Ensembl ID | ENSG00000115956 |
| UniProt ID | Q6P4Q7 |
| OMIM ID | 607805 |
| HGNC ID | 20293 |
| Aliases | ACDP4, FLJ20261, KIAA1592 |
Description
CNNM4 encodes a member of the cyclin and CBS domain divalent metal cation transport mediator family. The protein functions as a magnesium transporter, playing a critical role in maintaining cellular magnesium homeostasis. Mutations in this gene are associated with Jalili syndrome (cone-rod dystrophy and amelogenesis imperfecta) and isolated cone-rod dystrophy. CNNM4 is widely expressed, with highest levels in the retina, kidney, and tooth enamel epithelium.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Jalili syndrome (cone-rod dystrophy and amelogenesis imperfecta) | Loss-of-function mutations impair magnesium transport, leading to photoreceptor degeneration and enamel defects | OMIM #217080; multiple reports in ClinVar and literature |
| Cone-rod dystrophy (isolated) | Missense or nonsense mutations disrupt protein function, causing progressive vision loss | ClinVar; NCBI GeneReviews |
| Hypomagnesemia (secondary) | Impaired renal magnesium reabsorption due to CNNM4 dysfunction | Case reports in PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | 12.5 | Medium |
| Retina | 15.2 | High |
| Tooth (enamel epithelium) | 18.0 | High |
| Liver | 6.8 | Low |
| Brain | 5.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 8.1 | Moderate expression |
| ARPE-19 (retinal pigment epithelium) | 14.5 | High expression |
| HepG2 | 5.0 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1312C>T (p.Arg438*) | Nonsense | Rare | Loss of function; associated with Jalili syndrome |
| c.1762G>A (p.Gly588Arg) | Missense | Rare | Impaired magnesium transport; cone-rod dystrophy |
| c.1003C>T (p.Arg335Trp) | Missense | Rare | Dominant negative effect; isolated cone-rod dystrophy |
Mutation functional classification
Loss of Function (LOF)
Nonsense and frameshift mutations (e.g., p.Arg438*) lead to truncated protein and loss of magnesium transport activity, causing autosomal recessive Jalili syndrome.
Gain of Function (GOF)
No gain-of-function mutations have been reported for CNNM4.
Dominant Negative (DN)
Missense mutations such as p.Arg335Trp may exert dominant negative effects, disrupting oligomerization and transport function, associated with autosomal dominant cone-rod dystrophy.
View complete mutation data：
Gene Ontology (GO)
| • magnesium ion transmembrane transporter activity (GO:0015095) | • magnesium ion transport (GO:0015693) |
| • plasma membrane (GO:0005886) | • integral component of membrane (GO:0016021) |
| • transmembrane transport (GO:0055085) |
Pathways
• Magnesium transport pathway
• Ion homeostasis by CNNM family members
Protein Summary
The CNNM4 protein is a transmembrane magnesium transporter localized to the plasma membrane. It contains a cyclin domain and two CBS domains, which are involved in magnesium binding and transport regulation. The protein is essential for magnesium homeostasis in specialized tissues, particularly the retina and dental enamel. Loss of function leads to intracellular magnesium deficiency, triggering cellular stress and apoptosis in photoreceptors and ameloblasts.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CNNM4 Knockout HEK293 Cell Line | EDJ-KQ8536 | Human | 26504 | Details Get a Quote |
| CNNM4 Knockout A-549 Cell Line | EDJ-KQ34678 | Human | 26504 | Details Get a Quote |
| CNNM4 Knockout HCT 116 Cell Line | EDJ-KQ34679 | Human | 26504 | Details Get a Quote |
| CNNM4 Knockout HeLa Cell Line | EDJ-KQ34680 | Human | 26504 | Details Get a Quote |
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