Abstract
The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl‐CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia. LMBRD1 encodes for LMBD1, a predicted lysosomal cobalamin transport protein. In this study, we determine the physiological function of LMBRD1 during embryogenesis by generating Lmbrd1 deficient mice using the Cre/LoxP system. Complete loss of Lmbrd1 function is accompanied by early embryonic death in mice. Whole mount in situ hybridization studies against bone morphogenetic protein 4 and Nodal show that initial formation of the proximal–distal axis is unaffected in early embryonic stages whereas the initiation of gastrulation is disturbed shown by the expression pattern of even skipped homeotic gene 1 and fibroblast growth factor 8 in Lmbrd1 deficient mice. We conclude that intact function of LMBD1 is essential for the initiation of gastrulation.
Highlights
Cobalamin (Cbl) metabolism is essential for normal development and survival
We found Lmbrd1 ubiquitously expressed with strong signals in the primitive streak and in extraembryonic tissues at E7.5 (Fig. 1A)
Defects of intracellular Cbl metabolism are associated with deficiency of MeCbl and/or AdoCbl, and result in impaired erythrocyte formation or DNA synthesis
Summary
Cobalamin (Cbl) metabolism is essential for normal development and survival. The intracellular transport and modifications of Cbl depend on different steps: after endocytosis the Cbl-transcobalamin complex is delivered to the lysosomes, where it is processed into free Cbl and transcobalamin [1]. Cobalamin is transported through the lysosomal membrane and converted to either methylcobalamin (MeCbl) in the cytosol or adenosylcobalamin (AdoCbl) in the mitochondria [2]. MeCbl and AdoCbl are coenzymes for two metabolic reactions: the methylation of homocysteine to methionine catalysed by methionine synthase in the cytosol, and the conversion of methylmalonyl-CoA to succinyl-CoA catalysed by methylmalonyl-CoA mutase (mut) in the mitochondria [3]. Functional Cbl metabolism is essential for erythrocyte formation and DNA synthesis, and has an essential role in the human metabolism. Human Cbl deficiency results in a variety of clinical symptoms including megaloblastic anemia and mental retardation [3]. 10 defects of intracellular Cbl metabolism referring to different complementation groups have been described (cblA-cblG, cblJ, cblX and mut) [4, 5].
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