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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

  • Homocysteine and B-Vitamin Metabolism
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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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Abbreviations

ANOVA:

analysis of variance

BHMT:

betaine:homocysteine methyltransferase

EGL:

external granular layer

ERG:

electroretinogram

MTHFR:

methylenetetrahydrofolate reductase

OFFHBC:

OFF-hyperpolarizing bipolar cells

SEM:

standard error of the mean

SOP:

sum of oscillatory potentials

tHcy:

total plasma homocysteine

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Acknowledgments

This work was funded by the Canadian Institutes of Health Research. AKL was the recipient of a Montreal Children’s Hospital Research Institute Studentship. We are grateful to Timothy A. Garrow (University of Illinois) for carrying out BHMT activity measurements.

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Authors and Affiliations

  1. Departments of Human Genetics, Pediatrics, and Biology, McGill University–Montreal Children’s Hospital Research Institute, 4060 Ste. Catherine West, Room 200, Montreal, H3Z 2Z3, Canada

    Andrea K. Lawrance, Liyuan Deng, Xiaoling Wang & Rima Rozen

  2. Department of Ophthalmology, McGill University–Montreal Children’s Hospital Research Institute, Montreal, Canada

    Julie Racine & Pierre Lachapelle

Authors
  1. Andrea K. Lawrance
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  2. Julie Racine
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  3. Liyuan Deng
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  4. Xiaoling Wang
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  5. Pierre Lachapelle
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  6. Rima Rozen
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Corresponding author

Correspondence to Rima Rozen.

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Communicated by: Viktor Kozich

Competing interest: None declared

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Lawrance, A.K., Racine, J., Deng, L. et al. Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes. J Inherit Metab Dis 34, 147–157 (2011). https://doi.org/10.1007/s10545-010-9127-1

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  • DOI: https://doi.org/10.1007/s10545-010-9127-1

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