CblE type of homocystinuria due to methionine synthase reductase deficiency: Clinical and molecular studies and prenatal diagnosis in two families

AbstractThere are now four genetic mouse models that induce hyperhomocyst(e)inemia by decreasing the activity of an enzyme involved in homocysteine metabolism: cystathionine β-synthase, methylenetetrahydrofolate reductase, methionine synthase and methionine synthase reductase. While each enzyme deficiency leads to murine hyperhomocyst(e)inemia, the accompanying metabolic profiles are significantly and often unexpectedly, different. Deficiencies in cystathionine β-synthase lead to elevated plasma methionine, while deficiencies of the remaining three enzymes lead to hypomethioninemia. The liver [S-adenosylmethionine]/[S-adenosylhomocysteine] ratio is decreased in mice lacking methylenetetrahydrofolate reductase or cystathionine β-synthase, but unexpectedly increased in mice with deficiencies in methionine synthase or methionine synthase reductase. Folate pool imbalances are observed in complete methylenetetrahydrofolate reductase deficiency, where methyltetra-hydrofolate is a minor component, and in methionine synthase reductase deficiency, where methyltetrahydrofolate is increased relative to wild-type mice. These differences illustrate the potential diversity among human patients with hyperhomocyst(e)inemia, and strengthen the argument that the pathologies associated with the dissimilar forms of the condition will require different treatments.Clin Chem Lab Med 2007;45:1700–3.

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Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism

Human Molecular Genetics ◽

10.1093/hmg/8.11.2009 ◽

1999 ◽

Vol 8 (11) ◽

pp. 2009-2016 ◽

Cited By ~ 55

Author(s):

A Wilson

Keyword(s):

Molecular Basis ◽

Complementation Group ◽

Methionine Synthase ◽

Reductase Deficiency ◽

Methionine Synthase Reductase ◽

Cobalamin Metabolism

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cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression

Human Mutation ◽

10.1002/humu.20270 ◽

2005 ◽

Vol 26 (6) ◽

pp. 590-590

Author(s):

Petra Zavadáková ◽

Brian Fowler ◽

Terttu Suormala ◽

Zorka Novotna ◽

Peter Mueller ◽

...

Keyword(s):

Methionine Synthase ◽

Reductase Deficiency ◽

Methionine Synthase Reductase ◽

Functional Correction ◽

Minigene Expression

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Relationship between methionine synthase, methionine synthase reductase genetic polymorphisms and deep vein thrombosis among South Indians

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2008.021 ◽

2008 ◽

Vol 46 (1) ◽

Cited By ~ 16

Author(s):

Shaik Mohammad Naushad ◽

Mohamed Nurul Jain Jamal ◽

Chintakindi Krishna Prasad ◽

Akella Radha Rama Devi

Keyword(s):

Deep Vein Thrombosis ◽

Genetic Polymorphisms ◽

Methionine Synthase ◽

Vein Thrombosis ◽

Methionine Synthase Reductase ◽

South Indians ◽

Deep Vein

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Prenatal Diagnosis of 5,10-Methylenetetrahydrofolate Reductase Deficiency

New England Journal of Medicine ◽

10.1056/nejm198507043130116 ◽

1985 ◽

Vol 313 (1) ◽

pp. 50-51 ◽

Cited By ~ 15

Keyword(s):

Prenatal Diagnosis ◽

Methylenetetrahydrofolate Reductase ◽

Reductase Deficiency ◽

Methylenetetrahydrofolate Reductase Deficiency

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Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

Cephalalgia ◽

10.1177/0333102413477738 ◽

2013 ◽

Vol 33 (7) ◽

pp. 469-482 ◽

Cited By ~ 6

Author(s):

Kathryn A Roecklein ◽

Ann I Scher ◽

Albert Smith ◽

Tamara Harris ◽

Gudny Eiriksdottir ◽

...

Keyword(s):

Migraine With Aura ◽

Multiple Testing ◽

Haplotype Analysis ◽

Methylenetetrahydrofolate Reductase ◽

Population Based ◽

Methionine Synthase ◽

Association Testing ◽

Methionine Synthase Reductase ◽

Increased Risk ◽

Genes Encoding

Aims The C677T variant in the methylenetetrahydrofolate reductase ( MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase ( MTR; EC 2.1.1.13) and methionine synthase reductase ( MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache ( n = 367), migraine without aura ( n = 85), migraine with aura ( n = 167), and no headache ( n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population.

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Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily

Thrombosis and Haemostasis ◽

10.1160/th06-02-0082 ◽

2006 ◽

Vol 96 (08) ◽

pp. 154-159 ◽

Cited By ~ 7

Author(s):

Rosa-Maria Guéant-Rodriguez ◽

Guido Anello ◽

Rosario Spada ◽

Antonino Romano ◽

Adrian Fajardo ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Vitamin B12 ◽

Methylenetetrahydrofolate Reductase ◽

Methionine Synthase ◽

Italian Population ◽

Significant Independent Predictor ◽

Methionine Synthase Reductase ◽

Ischaemic Cerebrovascular Disease ◽

Folate And Vitamin B12 ◽

Neutral Effect

SummaryAssociation between methylenetetrahydrofolate reductase polymorphism (MTHFR 677 C>T), a determinant of homocysteine plasma level (t-Hcys), with ischaemc cerebrovascular disease (iCVD) seems to be neutral in North Europe and North America. The association of 2756 A>G of methionine synthase (MTR), 66 A>G of methionine synthase reductase (MTRR) and 776 C>G of transcobalamin (TCN2) needs to be evaluated further. It was the objective of this study to evaluate the association of these polymorphisms, t-Hcys, vitamin B12 and folate levels with iCVD, in an Italian population from Sicily. We investigated the association of these polymorphisms, t-Hcys, vitamin B12 and folate with iCVD in 252 subjects, including 131 cases and 121 sexand agematched healthy controls. t-Hcys was higher in the iCVD group than in controls [15.3 (11.5–17.9) vs. 11.6 (9.4–14.5) µM; P=0. 0007] and also in subjects withTCN2 776CG genotype, compared to homozygous genotypes [13.5 (9.9± 16.9) vs. 11.7 (9.6 ± 14.4) µM; P=0. 0327]. The folate level in cases and controls was consistent with an adequate dietary intake [12.7 (9.0–15.3) vs. 12.5 (9.6–16.9) nM; P=0. 7203]. In multivariate analysis, t-Hcys was a significant independent predictor of iCVD with an odds ratio of 1.14 (95% C.I. : 1.06–1.24; P=0. 0006). No association was found between MTHFR, MTR, MTRR and TCN2 polymorphisms and iCVD risk. We have found an influence of t-Hcys and a neutral effect of MTHFR, MTR, MTRR and TCN2 on iCVD risk in Sicily. The neutral influence of these polymorphisms may be explained by adequate status in folate and vitamin B12. Other factors underlying the increased t-Hcys need further investigations.

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