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Human Molecular Genetics Advance Access originally published online on October 18, 2006
Human Molecular Genetics 2006 15(23):3387-3393; doi:10.1093/hmg/ddl415
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice

Sheila Ernest1,2, Michelle Carter4, Haifeng Shao2,3, Angela Hosack5, Natalia Lerner6, Clemencia Colmenares6, David S. Rosenblatt5, Yoh-Han Pao2,3, M. Elizabeth Ross4 and Joseph H. Nadeau1,2,*

1 Department of Genetics, 2 Center for Computational Genomics and 3 Department of Electrical Engineering and Computer Science, Case Western Reserve University School of Medicine, 10900 Euclid Ave Cleveland, OH 44106 USA, 4 Department of Neurology and Neuroscience, Weill Medical College, Cornell University New York, NY, USA, 5 Departments of Human Genetics, Medicine, Pediatrics and Biology, McGill University, Montreal, Quebec, Canada and 6 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

* To whom correspondence should be addressed. Tel: +1 2163680581; Fax: +1 2163683832; Email: emailjhn4{at}case.edu

Received July 24, 2006; Revised September 12, 2006; Accepted October 10, 2006

Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplementation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail (Cd) mutant mice are an important model of folate-responsive NTDs. To identify features that are diagnostic for responsiveness versus resistance to dietary folate supplementation, we surveyed metabolite and expression levels in liver samples from folate-supplemented, folate-reduced and control diets in Cd mutant and wild-type adult females. Cd homozygotes had normal total homocysteine (tHcy) levels suggesting that folate suppresses NTDs through a mechanism that does not involve modulating serum tHcy levels. Instead, parallel changes in metabolite and expression profiles in folate-supplemented Cd/Cd homozygotes and folate-reduced +/+ and Cd/+ mice suggest that Crooked-tail homozygotes have a defect in the utilization of intracellular folate. Then, by combining these expression and metabolite profile results with published results for other models and their controls, two clusters were found, one of which included several folate-responsive NTD models and the other previously untested and presumably folate-resistant models. The predictive value of these profiles was verified by demonstrating that NTDs of Ski–/– mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation. These results raise the possibility of using metabolite and expression profiles to distinguish folate-responsive and resistance adult females who are at risk for bearing fetuses with an NTD.


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