MYORG

Myogenesis-regulating glycosidase is an enzyme that in humans is encoded by the MYORG gene.

MYORG is a human protein-coding gene on chromosome 9. It produces a type I membrane alpha glycosidase enzyme that is found mainly in the endoplasmic reticulum and the nuclear envelope.^[5][6] Changes affecting both copies (biallelic) of the MYORG gene that reduce or eliminate its function (loss-of-function) are a known autosomal recessive cause of primary familial brain calcification (PFBC). This condition is a neurodegenerative disorder marked by calcium deposits on both sides of the brain, along with a range of symptoms that can affect movement, balance (cerebellar function), and thinking ability.^{[7][8][9][10]} PFBC caused by MYORG variants forms a distinct subgroup that can be recognized clinically and on brain imaging. Unlike autosomal dominant forms of PFBC, this type follows a recessive inheritance pattern and usually occurs without abnormalities in calcium, phosphate, or parathyroid hormone levels in the body.^[8][9][10]

The MYORG gene is located on chromosome 9q21 and encodes a type I transmembrane glycoprotein. The protein comprises a luminal glycosidase domain within the internal space of organelles, a single transmembrane segment, and a short cytoplasmic tail.^[5][6][11]

The protein belongs to the glycoside hydrolase family 27 (GH27). Although it shares structural homology with α-galactosidases, it exhibits distinct active-site features that confer restricted substrate specificity.^[11] Structural and biochemical analyses indicate that the luminal domain adopts the TIM barrel fold characteristic of GH27 enzymes and contains conserved catalytic residues required for α-galactosidase-type activity.^[11]

MYORG localizes to the endoplasmic reticulum and the outer nuclear membrane. Its luminal domain faces the endoplasmic reticulum lumen, consistent with a role in processing glycoproteins within the secretory pathway.^[5][11][12]

MYORG is a glycosidase enzyme that was first studied for its role in myogenesis (muscle formation), where it may influence cell growth and signaling pathways such as those involving insulin-like growth factor 2 (IGF2).^[5] However, its relevance to disease is primarily linked to its function in the brain.

In the central nervous system, MYORG is highly expressed in S100B-positive astrocytes, a type of support cell that helps maintain the brain’s environment and supports neurons.^[12][13] This suggests that MYORG plays an important role in supporting the neurovascular unit, which regulates interactions between brain cells and blood vessels.

Biochemical studies indicate that MYORG functions as an α-galactosidase-like enzyme, helping to process specific sugar molecules (glycans) within the cell’s secretory pathway. Its activity appears to be limited to a narrow range of substrates, and its full set of natural targets is still being investigated.^[11]

Evidence from patients, experimental models, and gene expression studies indicates that MYORG is important for maintaining a stable environment in the brain. When MYORG does not function properly, this balance may be disrupted, contributing to abnormal calcium deposition around small blood vessels—a key feature of primary familial brain calcification.^[7][12][13]

Loss-of-function variants in MYORG are a major cause of autosomal recessive primary familial brain calcification (PFBC), sometimes termed MYORG-related PFBC.^{[7][8][9][10]} This disorder is characterized by abnormal deposits of calcium in the brain, most commonly affecting the basal ganglia, thalamus, dentate nuclei, and other regions visible on neuroimaging.^{[7][8][9][10]} Affected individuals often develop neurological symptoms such as movement disorders, dysarthria (difficulty speaking), and cerebellar ataxia (problems with coordination and balance). Some individuals may also experience cognitive decline or psychiatric symptoms.^{[7][8][9][10]} Unlike some other forms of PFBC, MYORG-related PFBC is inherited in an autosomal recessive pattern, meaning that affected individuals typically have two nonfunctional copies of the gene. It differs from autosomal dominant forms linked to genes such as SLC20A2, PDGFRB, PDGFB, and XPR1.^[8][9][10] Routine blood tests in people with MYORG-related PFBC usually show normal levels of calcium, phosphate, and parathyroid hormone. This indicates that the condition is not caused by a general problem with calcium metabolism, but rather by processes within the brain itself.^[8][9][10] The condition can vary in severity and age of onset. While many cases appear in adulthood, earlier onset in childhood has also been reported. Additional findings may include involvement of the brainstem, such as lesions in the pons, and a variable rate of progression over time.^{[8][9][13][10]}