ArticleThe Journal of biological chemistry
Functional mechanisms of MYRF DNA-binding domain mutations implicated in birth defects.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium leading to nanophthalmos.JCI insight · 2026Article
- Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp).Annals of clinical and translational neurology · 2026Article
- Anomalous Left Coronary Artery from the Pulmonary Artery in Three Patients with MYRF-Associated Cardiac-Urogenital Syndrome.Pediatric cardiology · 2025Article
- MYRF gene mutation leading to coronary artery anomaly combined with 46,XY sex development disorder, a case report and literature review.BMC pediatrics · 2025Review
- Discovery of oligodendrocyte enhancers that regulate Sox10 expression.PLoS genetics · 2025Article
- Genetic Spectrum and Genotype-Phenotype Correlations in a Chinese Cohort With Nanophthalmos With Secondary Angle-Closure Glaucoma.Investigative ophthalmology & visual science · 2025Article
- Uncovering oligodendrocyte enhancers that control Cnp expression.Human molecular genetics · 2023Article
- Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead.International journal of molecular sciences · 2023Review
- CRISPR-based knockout and base editing confirm the role of MYRF in heart development and congenital heart disease.Disease models & mechanisms · 2023Article
- Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?Molecular genetics & genomic medicine · 2023Article
- Article
- A Glance at the Molecules That Regulate Oligodendrocyte Myelination.Current issues in molecular biology · 2022Review
- Identifying oligodendrocyte enhancers governing Plp1 expression.Human molecular genetics · 2021Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Myrf is a pleiotropic membrane-bound transcription factor that plays critical roles in diverse organisms, including in oligodendrocyte differentiation, embryonic development, molting, and synaptic plasticity. Upon autolytic cleavage, the Myrf N-terminal fragment enters the nucleus as a homo-trimer and functions as a transcription factor. Homo-trimerization is essential for this function because it imparts DNA-binding specificity and affinity. Recent exome sequencing studies have implicated four de novo MYRF DNA-binding domain (DBD) mutations (F387S, Q403H, G435R, and L479V) in novel syndromic birth defects involving the diaphragm, heart, and the urogenital tract. It remains unknown whether and how these four mutations alter the transcription factor function of MYRF. Here, we studied them by introducing homologous mutations to the mouse Myrf protein. We found that the four DBD mutations abolish the transcriptional activity of the Myrf N-terminal fragment by interfering with its homo-trimerization ability by perturbing the DBD structure. Since the Myrf N-terminal fragment strictly functions as a homo-trimer, any loss-of-function mutation has the potential to act as a dominant negative. We observed that one copy of Myrf-F387S, Myrf-Q403H, or Myrf-L479V, but not Myrf-G435R, was tolerated by the Myrf N-terminal homo-trimer for structural and functional integrity. These data suggest that F387S, Q403H, and L479V cause birth defects by haploinsufficiency, while G435R does so via dominant negative functionality.
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