Long term goals of this project are to determine the biotin requires for normal individuals in circumstances in which biotin status may be impaired and to investigate the consequences and pathogenic mechanisms for marginal biotin deficiency. We recently demonstrated that marginal biotin deficiency is common during normal human gestation and have demonstrated that marginal deficiency is quite teratogenic in mice. Thus, the following five specific aims are relevant and timely.
In Specific Aim #1, we will test the hypothesis that maternal biotin deficiency causes abnormal development of fetal skeletons and palate by causing deficient fetal activity of the biotin-dependent enzyme acetyl- CoA carboxylase which leads in turn to deficiency of arachidonic acid and prostaglandin. In fetal palate and limb bud explants from biotin deficient and sufficient CD-1 mice, we will quantitative fetal arachidonic acid component and synthesis rates and will examine the malformation ameliorating effects of supplementation of arachidonic acid and prostaglandin and the amelioration blocking effects of cyclooxygenase inhibitors. Analogous studies will also be conducted in vivo.
In Specific Aim #2, we will test the hypothesis that infants with cleft plate or limb shortening have significantly reduced biotin status compared to normal infants. In a case-controlled study, biotin status will be assessed in cord blood using odd-chain fatty acid composition in red blood cell membranes and plasma and lymphocyte activity of the biotin-dependent enzyme propionyl-CoA carboxylase.
In Specific Aim #3, we will clone and sequence a biotin transporter recently discovered in our laboratory. In studies of cells from the first individual with biotin transporter deficiency, we will investigate the molecular nature of the genetic defect.
In Specific Aim #4, we will confirm promising new indicators of biotin status and investigate the validity of the expression of particular biotin- related genes (e.g., carboxylases) as indicators of marginal biotin deficiency in healthy adults rendered marginally biotin deficiency by egg-white feeding.
In Specific Aim #5, we will determine the subcellular localization of the enzyme(s) responsible for catalyzing the beta- oxidation of biotin to the inactive metabolite bisnorbiotin and characterize this pathway. Understanding of this pathway is important because accelerated biotin catabolism may be the major cause of biotin deficiency in pregnancy and anticonvulsants.
|Mock, Donald M (2017) Biotin: From Nutrition to Therapeutics. J Nutr 147:1487-1492|
|Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M (2015) In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency. J Nutr 145:32-40|
|Mock, Donald M (2014) Adequate intake of biotin in pregnancy: why bother? J Nutr 144:1885-6|
|Pindolia, Kirit; Li, Hong; Cardwell, Cisley et al. (2014) Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency. Mol Genet Metab 112:49-56|
|Hernández-Vázquez, A; Wolf, B; Pindolia, K et al. (2013) Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab 110:248-54|
|Bogusiewicz, Anna; Horvath, Thomas D; Stratton, Shawna L et al. (2012) Measurement of acylcarnitine substrate to product ratios specific to biotin-dependent carboxylases offers a combination of indicators of biotin status in humans. J Nutr 142:1621-5|
|Pindolia, Kirit; Jordan, Megan; Guo, Caiying et al. (2011) Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder. Mol Genet Metab 102:161-9|
|Horvath, Thomas D; Matthews, Nell I; Stratton, Shawna L et al. (2011) Measurement of 3-hydroxyisovaleric acid in urine from marginally biotin-deficient humans by UPLC-MS/MS. Anal Bioanal Chem 401:2805-10|
|Stratton, Shawna L; Horvath, Thomas D; Bogusiewicz, Anna et al. (2011) Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. J Nutr 141:353-8|
|Stratton, Shawna L; Horvath, Thomas D; Bogusiewicz, Anna et al. (2010) Plasma concentration of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. Am J Clin Nutr 92:1399-405|
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