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

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.

Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice

“…To that end, we comparatively analyzed regional brain homogenates from 22-month-old wt and het Mthfr mice fed an amino acid defined diet with normal folate content (normal folate diet, NF). Null Mthfr −/− mice could not be used in these studies, since mice with severe MTHFR deficiency die prematurely as a result of atherosclerosis and other complications (Chen et al, 2001; Lawrance et al, 2011). Similar to the effects of MTHFR deficiency in young Mthfr +/− mice (Figure 2), plasma tHcy levels were increased by an average of ~1.6-fold in old Mthfr +/− mice, relative to wt controls (Figure 5A).…”

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

“…Surprisingly, although retinopathy has been shown in a mouse model (Lawrance et al 2011) and eye involvement is frequent in other methylation disorders such as the cblC, cblE and cblG defect (Fischer et al 2014;Huemer et al 2014a, b), eye disease has rarely been reported in severe MTHFR deficiency (Ronge and Kjellman 1996). This study indicates that patients with severe MTHFR deficiency should regularly be monitored for eye disease since nystagmus, visual impairment and optic atrophy were present in this cohort in 18 % of cases and symptoms were considered burdensome in 50 % of these patients.…”

Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

“…For example, mice deficient in (or lacking) the enzyme methylene tetrahydrofolate reductase (MTHFR), which converts N 5 ,N 10 -methylenetetrahydrofolate into N 5 -methyltetrahydrofolate, the predominant circulating form of folate in the body, have high levels of homocysteine but no defect in the transsulfuration pathway. 41 These mice offer a handsome alternative tool for examining the consequences of excess homocysteine in the retina. With these mice in hand, we should be poised to dissect the role of hyperhomocysteinemia in retinal structure and function; studies are now under way to investigate this systematically.…”