MYRF and Associated Diseases
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Overview of MYRF
The myelin regulatory factor (MYRF) gene encodes an endoplasmic reticulum membrane protein that undergoes auto-processing to release its N-terminal fragment which enters the nucleus, forms a homo-trimer, and functions as a transcription factor. MYRF is also known as GM98 in mice and C11ORF9 in humans. MYRF contains a DNA-binding domain, an intramolecular chaperone auto-processing (ICA) domain, and a transmembrane domain. MYRF protein belongs to a class of membrane-bound transcription factors (TFs) that are translated as transmembrane proteins but then proteolysis occurs, releasing a soluble TF, which is transported to the nucleus to participate in transcriptional regulation.
Fig.1 Structural motifs conserved in human and mouse MYRF. (Huang, 2021)
Function of MYRF
MYRF was first noted to be a key transcription factor for oligodendrocyte differentiation and central nervous system myelination and has been previously shown to play a vital role in the normal maintenance of myelin by oligodendrocytes. MYRF can directly bind putative enhancer sequences of myelin genes, such as MP and Pulp, to induce their expression and together with the transcription factor Sox10, synergistically promote myelin gene expression. Recently, it has been reported that MYRF is a direct target gene of another differentiating factor, SOX10. Once induced by SOX10 at the beginning of oligodendrocytes (OLs) differentiation, MYRF redirects SOX10 to myelin genes but restrains it from OPC genes simultaneously to ensure its strict target selection. Genetic deletion of MYRF during development results in a near-complete failure to differentiate into late-stage myelinating oligodendrocytes. MYRF is expressed outside of the central nervous system, and there is increasing evidence that it plays a critical role in the development of various organs including the heart, lungs, diaphragm, and genitourinary tract.
Variants in MYRF are Associated with Human Disorders
MYRF is also expressed in the retinal pigment epithelium (RPE), a single layer of pigmented epithelial cells between the choroid and retina. Recently, a series of heterozygous variants in MYRF have been related to inheritable human ocular defects, such as nanophthalmos. Growing evidence indicates that MYRF variants are also associated with several human autosomal dominant disorders, including genitourinary abnormalities, congenital heart defects, lung dysplasia, and congenital diaphragmatic hernia. As in the case of nanophthalmos, MYRF mutations in these diseases were found in both N- and C-segments of MYRF, including the proline-rich domain, DNA binding domain, intramolecular chaperone auto-processing domain, and endoplasmic reticulum lumen region.
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Reference
- Huang, H.; et al. MYRF: A mysterious membrane-bound transcription factor involved in myelin development and human diseases. Neuroscience Bulletin. 2021, 37(6): 881-884.
