Alternative titles; symbols
HGNC Approved Gene Symbol: MYRF
SNOMEDCT: 1332387008;
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38) : 11:61,752,636-61,788,518 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.2 | Cardiac-urogenital syndrome | 618280 | Autosomal dominant | 3 |
| Encephalitis/encephalopathy, mild, with reversible myelin vacuolization | 618113 | Autosomal dominant | 3 | |
| Nanophthalmos 1 | 600165 | Autosomal dominant | 3 |
The MYRF gene encodes a transcription factor that acts as a myelin regulatory factor necessary for oligodendrocyte differentiation and the maintenance of mature oligodendrocytes and myelin structure (summary by Kurahashi et al., 2018).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned KIAA0954. RT-PCR ELISA detected moderate expression in brain, lung, ovary, and spinal cord, and in all specific brain regions examined except cerebellum. Low expression was detected in liver and pancreas, and little to no expression was found in heart, skeletal muscle, kidney, spleen, and testis.
In the course of constructing a transcript map of the region encompassing the BEST1 gene (607854), Stohr et al. (2000) identified C11ORF9. Using EST mapping, computational exon prediction, RT-PCR, and 5-prime RACE, they cloned the full-length cDNA from an eye tissue-specific cDNA library. The deduced 1,111-amino acid protein has a calculated molecular mass of 120 kD. The N-terminal half contains 2 proline-rich sequences, and the C-terminal half contains 2 transmembrane helices. Northern blot analysis detected a 5.7-kb transcript in lung and retinal pigment epithelial tissue and in a retinal pigment epithelial cell line. Minor expression was detected in cerebellum and retina. In addition, RT-PCR detected expression in brainstem, uterus, basal ganglion, and liver; no expression was detected in lymphocytes or heart. Examination of EST databases revealed widespread expression and tissue-specific abundance.
Garnai et al. (2019) analyzed RNA expression of MYRF in human ocular and adnexal tissues, and identified highest levels in the retinal pigment epithelium (RPE)/choroid and in the optic nerve, with low levels in other ocular tissues relative to extraocular muscle. A similar pattern of expression was observed in mouse ocular tissues with a 99.5-fold greater expression in RPE as compared to retina by qRT-PCR.
By RNAscope analysis in mouse, Luna et al. (2026) detected Myrf transcripts at embryonic day (E) 13.5 in the mesothelium outlining various organs and body cavities, including the lung and diaphragm, as well as in the lung epithelium.
Stohr et al. (2000) determined that the C11ORF9 gene contains 26 exons and spans 33.1 kb.
By genomic sequence analysis, Stohr et al. (2000) mapped the C11ORF9 gene to chromosome 11q12-q13.1, where it lies 4.3 kb centromeric to the FEN1 gene (600393).
In coimmunoprecipitation experiments in HEK293T cells, Garnai et al. (2019) were able to pull down TMEM98 with full-length MYRF and vice-versa, suggesting that these proteins interact directly. The authors observed that TMEM98 preferentially interacted with the uncleaved form of MYRF, and TMEM98 also stabilized uncleaved MYRF in a dose-dependent manner. Analysis of interactions of truncated MYRF with TMEM98 suggested that the region critical for this interaction lies downstream of the cleavage site in the intramolecular chaperone or transmembrane domains, between amino acids 586 and 846.
Aprato et al. (2020) investigated the mechanism by which MYRF cooperates with SOX10 (602229) during oligodendroglial development. EMSA analysis showed that high-affinity DNA binding of MYRF requires at least 2 CTGGCAC consensus motifs spaced 1 to 1.5 helical turns apart, consistent with MYRF functioning as a homotrimer. By luciferase reporter assays, Aprato et al. (2020) found that MYRF synergistically activated SOX10-responsive regulatory regions of oligodendrocyte-specific genes but inhibited SOX10-dependent activation of oligodendrocyte precursor cell (OPC)-specific genes. EMSA showed that MYRF bound to regulatory regions of the oligodendrocyte-specific genes but not to regulatory regions of the OPC-specific genes, indicating that the differential response correlates with the presence or absence of functional MYRF binding sites. Coimmunoprecipitation studies showed that MYRF physically interacts with SOX10; GST pulldown experiments demonstrated that this interaction involves the amino-terminal two-thirds of MYRF and the dimerization and DNA-binding domain of SOX10. Aprato et al. (2020) concluded that MYRF acts as a modulatory switch for SOX10 activity, allowing SOX10 to switch from OPC-specific target genes to oligodendrocyte-specific target genes during terminal differentiation by a combination of physical sequestration on genes lacking MYRF binding sites and synergistic coactivation on genes containing both SOX10 and MYRF binding sites.
Mild Encephalitis/Encephalopathy With Reversible Myelin Vacuolization
In 9 patients from 2 unrelated Japanese families with mild encephalitis/encephalopathy with reversible myelin vacuolization (MMERV; 618113), Kurahashi et al. (2018) identified a heterozygous missense mutation in the MYRF gene (Q403R; 608329.0001). The mutation, which was found by whole-exome sequencing in the first family and confirmed by Sanger sequencing in both families, segregated with the disorder in both families. Haplotype analysis suggested a founder effect. In vitro functional expression studies using a luciferase reporter showed that the mutation resulted in significantly decreased transcriptional activity. Since all patients had normal psychomotor development even after recurrent episodes, Kurahashi et al. (2018) suggested that the function of the MYRF variant is relatively preserved under normal circumstances, but is insufficient during increased physiologic demands, such as infection. Direct sequencing of the MYRF gene in 33 individuals with sporadic MMERV did not identify any pathogenic variants.
Cardiac-Urogenital Syndrome
In 2 unrelated boys with cardiac-urogenital syndrome (CUGS; 618280), Pinz et al. (2018) identified heterozygosity for de novo mutations in the MYRF gene, a splice site variant (608329.0002) and a nonsense mutation (R840X; 608329.0003), respectively.
In a male fetus with complex congenital heart disease and severe urogenital malformations, Chitayat et al. (2018) identified heterozygosity for a de novo frameshift variant in the MYRF gene (608329.0004).
Qi et al. (2018) reported 7 patients from 6 families with CUGS who had heterozygous mutations in the MYRF gene (see, e.g., 608329.0005 and 608329.0006).
Garnai et al. (2019) reported an 8-year-old boy with mitral valve prolapse, unilateral cryptorchidism, and micropenis, who showed ocular features consistent with nanophthalmos (see NNO1, 600165), who was heterozygous for a 1-bp duplication in the MYRF gene (608329.0008). His asymptomatic mother, who had a normal eye exam, was a mosaic carrier of the variant.
Nanophthalmos 1
In a large multigenerational family with nanophthalmos (NNO1; 600165) originally described by Othman et al. (1998), Garnai et al. (2019) identified heterozygosity for a splice site mutation in the MYRF gene (608329.0007) that segregated fully with disease and was not found in the gnomAD database.
From a cohort of 11 Chinese parent/child trios with nanophthalmos, Guo et al. (2019) identified 2 patients with de novo frameshift mutations, both at nucleotide 789 in the MYRF gene: 1 had a 1-bp deletion (608329.0009), and the other, a 1-bp duplication (608329.0010). Further screening of the MYRF gene in 3 trios and 10 sporadic nanophthalmos cases identified 1 proband with a missense mutation (R478P; 608329.0011) and 1 sporadic patient with a nonsense mutation (R986X; 608329.0012). The mutations were not found in public variant databases, and occurred at conserved residues.
Koenning et al. (2012) found that genetic ablation of the Mrf gene in mature oligodendrocytes in adult mice resulted in a delayed and severe demyelination. The mice had impaired motor skill learning. The demyelination was accompanied by microglial/macrophage infiltration, axonal damage, and decreased expression of myelin genes. However, over time, there was some evidence of remyelination. The findings demonstrated that ongoing expression of Mrf within the adult central nervous system is critical to maintain mature oligodendrocyte identity and the integrity of myelin.
Garnai et al. (2019) generated an MYRF loss-of-function mouse model in the early eye field. Patchy loss of RPE pigmentation was present as early as embryonic day (E) 15.5 in mutant eyes, and histologic analysis confirmed segmental loss of RPE granular pigment and thinning of the choroid. Evaluation of the outer retina showed shortened photoreceptor inner and outer segments (IS and OS) and thinning of the outer nuclear layer, especially overlying depigmented areas. Immunostaining for rhodopsin (180380) and cone arrestin (301770) revealed a statistically significant loss of IS/OS area compared to total retinal area in homozygous mutants compared to controls, and a preferential loss of cone photoreceptors. At 10 months of age, fundus photography in homozygotes showed patchy areas of RPE and retinal atrophy, with heterozygotes showing smaller but similar-looking lesions. On spectral-domain optical coherence tomography (SD-OCT) in homozygous mutant eyes, there was evidence of outer retinal disruption, with severe loss of the ONL and RPE in affected areas in the retinal periphery and milder changes centrally; electroretinography revealed significantly diminished scotopic and photopic responses. Heterozygous eyes did not show histologic, ERG, or SD-OCT abnormalities at 10 months of age. Analysis of nanophthalmos-associated RPE-expressed genes revealed significantly reduced levels of Tmem98 (615949) in homozygous mutant eyes compared to heterozygotes or controls. Immunostaining demonstrated a profound reduction in Tmem98 protein, both early in development and persisting through later stages.
Luna et al. (2026) investigated the role of Myrf in lung development and congenital diaphragmatic hernia in mice. Inactivation of Myrf at E6.5, at the start of lung development, resulted in fully penetrant left-sided congenital diaphragmatic hernia with herniation of abdominal contents into the chest cavity, and mutants died shortly after birth. Mutant lungs were hypoplastic, misshapen, and not inflated with air at birth. Inactivation of Myrf specifically in diaphragm fibroblasts did not cause diaphragm or lung abnormalities, whereas inactivation specifically in mesothelium caused diaphragmatic defects and organ herniation, indicating that Myrf is required in the diaphragm mesothelium. In contrast, epithelial-specific inactivation of Myrf resulted in viable mice with normal lung histology at postnatal day 39 and 1 year of age, indicating that Myrf is not required in the lung epithelium. By lineage tracing and single-cell RNA sequencing, Luna et al. (2026) showed that mesothelial cells in the normal developing lung are multipotent progenitors for lung mesenchymal cells. In the absence of Myrf, mesothelial cells showed increased differentiation into mesenchymal cell types at the expense of self-renewal, suggesting that MYRF constrains mesothelial cell progenitor properties. Analysis of compound mutants showed that MYRF functions synergistically with Yap1 (606608) and Wwtr1 (TAZ; 607392) in mesothelium differentiation. Inactivation of Myrf at E12.5 to bypass herniation resulted in mice that survived postnatally but showed mesothelial thickening, ectopic smooth muscle bundles at the lung periphery, significant elastin (ELN; 130160) accumulation, and impaired respiratory mechanics. Luna et al. (2026) concluded that MYRF is a key transcriptional regulator of mesothelial cell fate, signaling, and plasticity.
In 9 affected individuals from 2 unrelated Japanese families, one of which (family B) was previously reported by Imamura et al. (2010), with mild encephalitis/encephalopathy with reversible myelin vacuolization (MMERV; 618113), Kurahashi et al. (2018) identified a heterozygous c.1208A-G transition (c.1208A-G, NM_001127392) in the MYRF gene, resulting in a gln403-to-arg (Q403R) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing in the first family and confirmed by Sanger sequencing in both families, segregated with the disorder in both families. The variant was not found in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or among a cohort of Japanese control individuals. Haplotype analysis suggested a founder effect. In vitro functional expression studies using a luciferase reporter showed that the mutation resulted in significantly decreased transcriptional activity.
In a 3-year-old boy with cardiac-urogenital syndrome (CUGS; 618280), Pinz et al. (2018) identified heterozygosity for a de novo splice site mutation (c.2336+1G-A, NM_001127392.2) within the transmembrane domain of the MYRF gene. The mutation was not found in the gnomAD database.
In a male infant who died at 10 days of life with cardiac-urogenital syndrome (CUGS; 618280), Pinz et al. (2018) identified heterozygosity for a de novo c.2518C-T transition (c.2518C-T, NM_001127392.2) in the MYRF gene, resulting in an arg840-to-ter (R840X) substitution. The mutation was not found in the gnomAD database.
In a male fetus with cardiac-urogenital syndrome (CUGS; 618280), Chitayat et al. (2018) identified heterozygosity for a de novo 2-bp duplication (c.1254_1255dupGA, NM_001127392.2) in the MYRF gene, causing a frameshift predicted to result in a premature termination codon (Thr419ArgfsTer14).
In a 46,XX patient (01-0429) with cardiac-urogenital syndrome (CUGS; 618280), Qi et al. (2018) identified heterozygosity for a c.1303G-A transition (c.1303G-A, NM_001127392.2) in the MYRF gene, predicted to result in a gly435-to-arg (G435R) substitution at a highly conserved residue within the DBD domain. The mutation was not found in the ExAC or gnomAD databases. In addition to ventricular septal defect and blind-ending vagina with absence of internal genital organs, the patient had a congenital left diaphragmatic hernia and accessory spleen.
In a 46,XY patient (05-0050) with cardiac-urogenital syndrome (CUGS; 618280), Qi et al. (2018) identified heterozygosity for a c.2084G-A transition (c.2084G-A, NM_001127392.2) in the MYRF gene, predicted to result in an arg695-to-his (R695H) substitution at a conserved residue within the ICA domain. The mutation was not found in the ExAC or gnomAD databases. In addition to hypoplastic left heart syndrome, ambiguous genitalia, and undescended testes, the patient had congenital diaphragmatic hernia and intellectual disability with motor delay.
In a large multigenerational family with nanophthalmos (NNO1; 600165) originally described by Othman et al. (1998), Garnai et al. (2019) identified heterozygosity for a splice site mutation (c.3376-1G-A, NM_001127392.2) in intron 26 of the MYRF gene that segregated fully with disease and was not found in the gnomAD database. RT-PCR showed that stable mRNA is generated, and the splice mutation was predicted to cause a 1-bp frameshift in the coding sequence, resulting in replacement of the final 26 amino acids of the protein with 30 different amino acids and disruption of a putative glycosylation site.
In an 8-year-old boy with mitral valve prolapse, unilateral cryptorchidism, and micropenis (CUGS; 618280), who also showed ocular features consistent with nanophthalmos (see NNO1, 600165), Garnai et al. (2019) identified heterozygosity for a 1-bp duplication (c.769dupC, NM_001127392.2) in the MYRF gene, causing a frameshift predicted to result in a premature termination codon (Ser264GlnfsTer74). His asymptomatic mother, who had a normal eye exam, was a mosaic carrier of the variant, which was not found in the gnomAD database.
In a 16-year-old Chinese girl (patient 8) with nanophthalmos (NNO1; 600165), Guo et al. (2019) identified heterozygosity for a de novo 1-bp deletion (c.789delC, NM_001127392) in the MYRF gene, causing a frameshift (Ser264fs) predicted to result in a premature termination codon at residue 271. The variant was not found in the ESP6500siv2, 1000 Genomes Project, or gnomAD databases.
In a 30-year-old Chinese woman (patient 10) with nanophthalmos (NNO1; 600165), Guo et al. (2019) identified heterozygosity for a de novo 1-bp duplication (c.789dupC, NM_001127392) in the MYRF gene, causing a frameshift (ser264fs) predicted to result in a premature termination codon at residue 337. The variant was not found in the ESP6500siv2, 1000 Genomes Project, or gnomAD databases.
In a 35-year-old Chinese woman (patient V1) with nanophthalmos (NNO1; 600165), Guo et al. (2019) identified heterozygosity for a c.1433G-C transition (c.1433G-C, NM_001127392) in the MYRF gene, resulting in an arg478-to-pro (R478P) substitution at a conserved residue. The variant was not found in the ESP6500siv2, 1000 Genomes Project, ExAC, or gnomAD databases.
In a 32-year-old Chinese man (sporadic patient 2) with nanophthalmos (NNO1; 600165), Guo et al. (2019) identified heterozygosity for a c.2956C-T transition (c.2956C-T, NM_001127392) in the MYRF gene, resulting in an arg986-to-ter (R986X) substitution. The variant was not found in the ESP6500siv2, 1000 Genomes Project, ExAC, or gnomAD databases.
Aprato, J., Sock, E., Weider, M., Elsesser, O., Frob, F., Wegner, M. Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development. Nucleic Acids Res. 48: 1254-1270, 2020. [PubMed: 31828317] [Full Text: https://doi.org/10.1093/nar/gkz1158]
Chitayat, D., Shannon, P., Uster, T., Nezarati, M. M., Schnur, R. E., Bhoj, E. J. An additional individual with a de novo variant in myelin regulatory factor (MYRF) with cardiac and urogenital anomalies: further proof of causality: comments on the article by Pinz et al. (2018). Am. J. Med. Genet. 176A: 2041-2043, 2018. [PubMed: 30070761] [Full Text: https://doi.org/10.1002/ajmg.a.40360]
Garnai, S. J., Brinkmeier, M. L., Emery, B., Aleman, T. S., Pyle, L. C., Veleva-Rotse, B., Sisk, R. A., Rozsa, F. W., Ozel, A. B., Li, J. Z., Moroi, S. E., Archer, S. M., and 18 others. Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genet. 15: e1008130, 2019. [PubMed: 31048900] [Full Text: https://doi.org/10.1371/journal.pgen.1008130]
Guo, C., Zhao, Z., Chen, D., He, S., Sun, N., Li, Z., Liu, J., Zhang, D., Zhang, J., Li, J., Zhang, M., Ge, J., Liu, X., Zhang, X., Fan, Z. Detection of clinically relevant genetic variants in Chinese patients with nanophthalmos by trio-based whole-genome sequencing study. Invest. Ophthal. Vis. Sci. 60: 2904-2913, 2019. [PubMed: 31266062] [Full Text: https://doi.org/10.1167/iovs.18-26275]
Imamura, T., Takanashi, J., Yasugi, J., Terada, H., Nishimura, A. Sisters with clinically mild encephalopathy with a reversible splenial lesion (MERS)-like features; familial MERS? J. Neurol. Sci. 290: 153-156, 2010. [PubMed: 20042198] [Full Text: https://doi.org/10.1016/j.jns.2009.12.004]
Koenning, M., Jackson, S., Hay, C. M., Faux, C., Kilpatrick, T. J., Willingham, M., Emery, B. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J. Neurosci. 32: 12528-12542, 2012. [PubMed: 22956843] [Full Text: https://doi.org/10.1523/JNEUROSCI.1069-12.2012]
Kurahashi, H., Azuma, Y., Masuda, A., Okuno, T., Nakahara, E., Imamura, T., Saitoh, M., Mizuguchi, M., Shimizu, T., Ohno, K., Okumura, A. MYRF is associated with encephalopathy with reversible myelin vacuolization. Ann. Neurol. 83: 98-106, 2018. [PubMed: 29265453] [Full Text: https://doi.org/10.1002/ana.25125]
Luna, G., Verheyden, J. M., Tan, C., Kim, E., Zhu, Z., Hwa, M., Sahi, J., Shen, Y., Chung, W. K., McCulley, D. J., Sun, X. MYRF controls mesothelium specification, signaling, and plasticity in lung development. Dev. Cell 61: 536-552, 2026. [PubMed: 41558485] [Full Text: https://doi.org/10.1016/j.devcel.2025.12.011]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
Othman, M. I., Sullivan, S. A., Skuta, G. L., Cockrell, D. A., Stringham, H. M., Downs, C. A., Fornes, A., Mick, A., Boehnke, M., Vollrath, D., Richards, J. E. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am. J. Hum. Genet. 63: 1411-1418, 1998. [PubMed: 9792868] [Full Text: https://doi.org/10.1086/302113]
Pinz, H., Pyle, L. C., Li, D., Izumi, K., Skraban, C., Tarpinian, J., Braddock, S. R., Telegrafi, A., Monaghan, K. G., Zackai, E., Bhoj, E. J. De novo variants in myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. Am. J. Med. Genet. 176A: 969-972, 2018. [PubMed: 29446546] [Full Text: https://doi.org/10.1002/ajmg.a.38620]
Qi, H., Yu, L., Zhou, X., Wynn, J., Zhao, H., Guo, Y., Zhu, N., Kitaygorodsky, A., Hernan, R., Aspelund, G., Lim, F.-Y., Crombleholme, T., and 17 others. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 14: e1007822, 2018. Note: Electronic Article. [PubMed: 30532227] [Full Text: https://doi.org/10.1371/journal.pgen.1007822]
Stohr, H., Marquardt, A., White, K., Weber, B. H. F. cDNA cloning and genomic structure of a novel gene (C11orf9) localized to chromosome 11q12-q13.1 which encodes a highly conserved, potential membrane-associated protein. Cytogenet. Cell Genet. 88: 211-216, 2000. [PubMed: 10828591] [Full Text: https://doi.org/10.1159/000015552]