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 |
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.
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).
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).
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.
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.
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]
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]
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]
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]