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Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes
Author(s) -
Lawrance Andrea K.,
Racine Julie,
Deng Liyuan,
Wang Xiaoling,
Lachapelle Pierre,
Rozen Rima
Publication year - 2011
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-010-9127-1
Subject(s) - methylenetetrahydrofolate reductase , medicine , endocrinology , biology , hyperhomocysteinemia , homocysteine , allele , genetics , gene
Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later‐onset neurological impairment, including developmental delay, motor dysfunction, and seizures. We previously characterized BALB/c Mthfr −/− mice as a model for this disorder and have recently backcrossed the disrupted allele onto the C57Bl/6 background to examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr −/− mice, C57Bl/6 Mthfr −/− mice have enhanced survival rates (81% vs 26.5%). Four‐day‐old BALB/c mutant pups had lower body, brain, and spleen weights relative to their wild‐type counterparts compared with C57Bl/6 mutants. Pregnant BALB/c Mthfr +/− mice had increased resorptions and embryonic delays compared with wild‐type littermates, whereas these outcomes in C57Bl/6 c Mthfr +/− mice were similar to those of wild‐type C57Bl/6 mice. BALB/c‐mutant pups had altered hematological profiles (higher hematocrit, hemoglobin, and white blood cell counts, with lower platelet counts) compared with C57Bl/6 mutants. Mutants of both strains had similar degrees of hepatic steatosis, hepatic activity of betaine:homocysteine methyltransferase, and altered cerebellar histology. Electroretinograms (ERG) in C57Bl/6 Mthfr −/− mice revealed decreased amplitude of scotopic and photopic waves in 6‐week‐old mice, with normalized ERGs at 13 weeks. Plasma homocysteine was modestly higher in C57Bl/6 compared with BALB/c mice. Our results emphasize the variable presentation of MTHFR deficiency in different genetic backgrounds and suggest that plasma homocysteine is not a predictor of severity. In addition, our novel findings of decreased spleen weights, thrombocytopenia, and impaired retinal function warrant investigation in patients with severe MTHFR deficiency or other forms of homocystinuria.