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Reference Guide
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HEPACAM
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HEPACAM

The HEPACAM gene encodes HepaCAM (also known as GlialCAM), a transmembrane glycoprotein involved in cell adhesion, signaling, and protein trafficking. 

Although first identified in liver cells, its critical roles in astrocyte development, junctional stability, and tumor suppression have made it a focus of both neurological and cancer research.

What is HEPACAM (Hepatic and Glial Cell Adhesion Molecule)?

The HEPACAM gene encodes HepaCAM, or GlialCAM, a single-pass type I transmembrane glycoprotein belonging to the immunoglobulin superfamily (IgSF). 

Although initially identified in hepatic tissue, HepaCAM is most prominently expressed in glial cells of the central nervous system (CNS), where it regulates astrocyte morphogenesis, junctional organization, and neuron-glia interactions. 

It also plays a role in epithelial tissue, particularly in the context of tumor suppression.

HEPACAM: A Cell Adhesion Molecule

HEPACAM produces a 416-amino acid glycoprotein with two extracellular Ig-like domains, a transmembrane domain, and a cytoplasmic tail rich in phosphorylation sites. The cytoplasmic domain is critical for downstream signaling that mediates cytoskeletal dynamics and cell migration.

HepaCAM exists as cis-homodimers at the cell surface and participates in larger protein complexes, including with MLC1, ClC-2, TRPV4, AQP4, and ATP1B1. These interactions influence both membrane protein trafficking and cellular response to osmotic stress.

Cell Adhesion and Interactions

HEPACAM is involved in the following cellular interactions:

Liver Cells (Hepatocytes)

In hepatocytes, HepaCAM facilitates cell spreading, attachment, and migration on extracellular matrix proteins like fibronectin and matrigel. Its expression is often reduced or silenced in hepatocellular carcinoma (HCC), suggesting a tumor suppressor role via regulation of adhesion and motility.

Glial Cells (Brain)

In astrocytes, HepaCAM localizes to cell-cell junctions and helps traffic key membrane proteins such as MLC1 and ClC-2

It stabilizes Connexin 43 (Cx43), the primary gap junction protein in glia, by promoting its membrane localization and preventing lysosomal degradation. This is essential for maintaining astrocyte-astrocyte coupling, inhibitory synapse density, and balanced excitatory/inhibitory signaling.

Functions

HepaCAM regulates:

Loss of HepaCAM leads to impaired astrocyte branching, disorganized white matter, and synaptic dysregulation, contributing to neurologic disease.

When is HEPACAM Testing Relevant?

HEPACAM testing may be considered in the following scenarios:

Research Studies on Cancer

HEPACAM downregulation has been implicated in multiple cancer types:

Research on Neurological Disorders

HEPACAM mutations or dysregulation are being studied in:

  • Megalencephalic leukoencephalopathy with subcortical cysts (MLC)
  • Multiple sclerosis (MS): Molecular mimicry between HepaCAM and EBV antigens may elicit autoimmune responses.

Not a Routine Diagnostic Test

HEPACAM testing is currently not part of routine clinical diagnostics and is primarily used in research or genetic analysis for leukodystrophies.

HEPACAM Genetic Testing: Test Procedure and Interpretation

Testing for HEPACAM is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for HEPACAM genetic testing are considered to be without mutations that can alter the activity of the HEPACAM proteins.

What Do Altered Levels of HEPACAM Mean?

Altered levels of HEPACAM may have the following meanings:

Cancer

Reduced HEPACAM in HCC may be associated with aggressive behavior and poorer prognosis.

In other tumors, the role of HEPACAM is context-specific and may involve impaired adhesion, increased migration, and loss of tumor-suppressive signaling.

Neurological Disorders

In MLC, mutations disrupt protein oligomerization and trafficking, especially affecting MLC1, MLC 2A and MLC 2B.

In astrocytes, loss of HepaCAM impairs junctional integrity and synaptic regulation.

What Does the Absence of Specific Studied HEPACAM Variations Mean?

The absence of known pathogenic HEPACAM variants does not rule out disease, particularly in polygenic or multifactorial conditions. Interpretation must account for:

  • Clinical context and family history
  • Other genetic and environmental factors
  • Comprehensive genomic analysis

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See References

Arnedo T, López-Hernández T, Jeworutzki E, Capdevila-Nortes X, Sirisi S, Pusch M, Estévez R. Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy. Hum Mutat. 2014 Oct;35(10):1175-8. doi: 10.1002/humu.22622. Epub 2014 Aug 18. PMID: 25044933.

Baldwin KT, Tan CX, Strader ST, Jiang C, Savage JT, Elorza-Vidal X, Contreras X, Rülicke T, Hippenmeyer S, Estévez R, Ji RR, Eroglu C. HepaCAM controls astrocyte self-organization and coupling. Neuron. 2021 Aug 4;109(15):2427-2442.e10. doi: 10.1016/j.neuron.2021.05.025. Epub 2021 Jun 24. PMID: 34171291; PMCID: PMC8547372.

Entry - *611642 - HEPATOCYTE CELL ADHESION MOLECULE; HEPACAM - OMIM. (2022). Omim.org. https://omim.org/entry/611642

Gene Database. (2025). HEPACAM Gene - GeneCards | HECAM Protein | HECAM Antibody. Genecards.org. https://www.genecards.org/cgi-bin/carddisp.pl?gene=HEPACAM

HEPACAM gene: MedlinePlus Genetics. (n.d.). Medlineplus.gov. https://medlineplus.gov/genetics/gene/hepacam/

HEPACAM hepatic and glial cell adhesion molecule [Homo sapiens (human)] - Gene - NCBI. (2025). Nih.gov. https://www.ncbi.nlm.nih.gov/gene/220296

Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022 Mar;603(7900):321-327. DOI: 10.1038/s41586-022-04432-7. PMID: 35073561; PMCID: PMC9382663.

Mei Chung Moh, Zhang, C., Luo, C., Lay Hoon Lee, & Shen, S. (2005). Structural and Functional Analyses of a Novel Ig-like Cell Adhesion Molecule, hepaCAM, in the Human Breast Carcinoma MCF7 Cells. Journal of Biological Chemistry, 280(29), 27366–27374. https://doi.org/10.1074/jbc.m500852200

Wu M, Moh MC, Schwarz H. HepaCAM associates with connexin 43 and enhances its localization in cellular junctions. Sci Rep. 2016 Nov 7;6:36218. doi: 10.1038/srep36218. PMID: 27819278; PMCID: PMC5098153.

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