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Production and Characterization of Maple Syrup Urine Disease Murine Models
Author(s) -
Skvorak Kristen J,
Paul Harbhajan S,
Ferguson Carolyn,
Watkins Simon,
Homanics Gregg E
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a448-a
Subject(s) - maple syrup urine disease , transgene , genetically modified mouse , amino acid , disease , glutamine , leucine , newborn screening , gene , medicine , biology , endocrinology , biochemistry , chemistry
Maple Syrup Urine Disease (MSUD) is a genetic disorder caused by deficiency of branched‐chain á‐keto acid dehydrogenase (BCKDH) and results in neurological impairment and death. Current unsatisfactory treatment options require improved therapies to combat this disease. However, the development of novel treatments is hindered by a lack of a suitable animal model. The study objective was to create genetically engineered murine models that mimic the human disease pathology of classic and intermediate MSUD. The model for classic MSUD (cMSUD) was created by targeted inactivation of the E2 subunit gene of BCKDH. cMSUD mice lacked BCKDH enzymatic activity, E2 immunoreactivity, and had a near 3‐fold increase in branched chain amino acids (BCAAs) in the blood. These metabolic derangements resulted in neonatal lethality. Results obtained are similar to that observed in cMSUD patients. The model of intermediate MSUD (iMSUD) was created by partial transgenic rescue of the E2 gene knockout. Transgene derived human E2 was sufficient to allow for survival, but was insufficient to normalize blood amino acid levels. Surviving iMSUD mice with BCAA levels that were intermediate between wildtype and the cMSUD mouse model were similar to that observed in iMSUD patients. We conclude that these mice represent very useful models of cMSUD and iMSUD and will allow for the development of novel treatment approaches, such as gene or stem cell therapies, to ultimately cure MSUD. This work was supported by NIH grants R43 DK57386, R43 DK57956, and the MSUD Family Support Group.