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J Inherit Metab Dis. 2011 Feb;34(1):147-57. doi: 10.1007/s10545-010-9127-1. Epub 2010 Jun 8.

Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes.

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Departments of Human Genetics, Pediatrics, and Biology, McGill University-Montreal Children's Hospital Research Institute, Montreal, H3Z 2Z3, Canada.


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.

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