Ronin (Thap11) Deficiency Results in a Disease Impacting both Vitamin B12 Metabolism and Ribosome Biogenesis

Abstract

Combined methylmalonic acidemia and homocystinuria (cblC type), a form of inherited intracellular vitamin B12 deficiency, is a rare metabolic and multi‐systemic disorder caused by mutations in MMACHC. Patients with cblC can have severe neurodevelopmental defects including microcephaly, hydrocephaly and seizures as well as renal, cardiac and hematological defects. Mutations in MMACHC have been the sole known causes of cblC, until recently when an X‐linked variant of the disease was described, termed cblX. This variant was found to be due to mutations in the X‐linked gene coding for the transcription cofactor HCFC1, which is known to be an obligatory partner for the transcription factor RONIN (THAP11). Intriguingly, a single patient exhibiting cblX‐like findings has been found to carry a mutation in RONIN. Patients, with both HCFC1 and RONIN mutations, were shown to have a dramatic reduction in MMACHC transcription. We have previously shown that the Hcfc1/Ronin transcriptional complex directly regulates mouse Mmachc expression. These findings suggest that cblX and the new Ronin (THAP11) disorder comprise a novel family of rare and severe cblC‐like disorders that are transcriptional in nature. As a result, we have generated a mouse model that carries the human mutation in Ronin (RoninF80L), in an effort to better understand the cellular mechanisms underlying the pathophysiology of these devastating neurodevelopmental diseases. Here we report the generation of the first mouse model, RoninF80L along with its phenotypic and molecular characterization. RoninF80L homozygous mice die soon after birth and exhibit severe brain developmental defects that recapitulate those observed in the human cblX and Ronin‐deficient patients. Moreover, consistent with a vitamin B12 deficiency, cells from RoninF80L homozygous embryos exhibit defects in cobalamin metabolism. Surprisingly however, RNA‐seq and ChIP‐seq analyses also revealed a role for ribosome biogenesis in the pathophysiology of the disease. Furthermore, we were able to show that there is also a functional deficit in ribosome biogenesis and hence protein translation. This identifies for the first time, a role for Ronin in ribosome biogenesis. Together the phenotypic and molecular data confirm that the RoninF80L mouse model will serve as a powerful tool to further uncover the pathophysiology of this complex family of diseases.Support or Funding InformationBaylor College of Medicine, Department of Molecular Physiology and Biophysics (Seed)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.