Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type

Dev Biol. 2020 Dec 1;468(1-2):1-13. doi: 10.1016/j.ydbio.2020.09.005. Epub 2020 Sep 14.


Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Here, we report the generation and characterization of two new mouse models to study the role of MMACHC in vivo. CRISPR/Cas9 genome editing was used to develop a Mmachc floxed allele (Mmachcflox/flox), which we validated as a conditional null. For a gain-of-function approach, we generated a transgenic mouse line that over-expresses functional Mmachc (Mmachc-OE+/tg) capable of rescuing Mmachc homozygous mutant lethality. Surprisingly, our data also suggest that these mice may exhibit a partially penetrant maternal-effect rescue, which might have implications for in utero therapeutic interventions to treat cblC. Both the Mmachcflox/flox and Mmachc-OE+/tg mouse models will be valuable resources for understanding the biological roles of MMACHC in a variety of tissue contexts and allow for deeper understanding of the pathophysiology of cblC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Homocystinuria* / genetics
  • Homocystinuria* / metabolism
  • Homocystinuria* / pathology
  • Homocystinuria* / physiopathology
  • Mice
  • Mice, Transgenic
  • Oxidoreductases* / genetics
  • Oxidoreductases* / metabolism
  • Vitamin B 12 Deficiency / congenital*
  • Vitamin B 12 Deficiency / genetics
  • Vitamin B 12 Deficiency / metabolism
  • Vitamin B 12 Deficiency / pathology
  • Vitamin B 12 Deficiency / physiopathology


  • Mmachc protein, mouse
  • Oxidoreductases

Supplementary concepts

  • Methylmalonic acidemia with homocystinuria