TY - JOUR
T1 - Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type
AU - Chern, Tiffany
AU - Achilleos, Annita
AU - Tong, Xuefei
AU - Hsu, Chih Wei
AU - Wong, Leeyean
AU - Poché, Ross A.
N1 - Funding Information:
We thank the Optical Imaging and Vital Microscopy (OIVM) and Genetically Engineered Mouse Core facilities at Baylor College of Medicine, and the Baylor Genetics Biochemical Genetics Laboratory for their services. This work was supported by grants from the National Institutes of Health : R01 EY024906 and R01 DE028298 to Ross Poché and T32 EY007102 to Graeme Mardon (supporting Tiffany Chern).
Funding Information:
We thank the Optical Imaging and Vital Microscopy (OIVM) and Genetically Engineered Mouse Core facilities at Baylor College of Medicine, and the Baylor Genetics Biochemical Genetics Laboratory for their services. This work was supported by grants from the National Institutes of Health: R01 EY024906 and R01 DE028298 to Ross Poch? and T32 EY007102 to Graeme Mardon (supporting Tiffany Chern).
Publisher Copyright:
© 2020 The Authors
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091232238&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2020.09.005
DO - 10.1016/j.ydbio.2020.09.005
M3 - Article
C2 - 32941884
AN - SCOPUS:85091232238
SN - 0012-1606
VL - 468
SP - 1
EP - 13
JO - Developmental Biology
JF - Developmental Biology
IS - 1-2
ER -