Lmbrd1 expression is essential for the initiation of gastrulation

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.

Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

“…However, Buers et al showed that Lmbd1 is also important for initiation of gastrulation and formation of mesodermal structures in early embryogenesis. Nodal , which encodes an important signal protein in formation of left-right axis, has been shown to be expressed slightly broader in whole-mount in-situ hybridization of Lmbd1 deficient mice, but with his typical proximal-distal gradient [ 34 ]. Finally, LMBRD1 could play a major role in establishing left-right axis during embryogenesis because of its impact on gastrulation and formation of mesodermal structures [ 34 ].…”

“…Nodal , which encodes an important signal protein in formation of left-right axis, has been shown to be expressed slightly broader in whole-mount in-situ hybridization of Lmbd1 deficient mice, but with his typical proximal-distal gradient [ 34 ]. Finally, LMBRD1 could play a major role in establishing left-right axis during embryogenesis because of its impact on gastrulation and formation of mesodermal structures [ 34 ]. Interestingly, so far reported individuals with metabolic disorders in cobalamin metabolism had homozygous deletions or canonical splice site variants in LMBRD1 .…”

Organic Acidemias: Clinical Presentation in Neonates

“…9 There could be associated mutations in cobalamin metabolism; CbIA disease involves the MMAA gene; CbIB disease the MMAB; CbIC-disease the MMACHC; CbID disease the MMADHC; CBIE disease the MTRR; CbIF disease the LMBD1 gene; and the CbIG disease is rooted in the MTR gene. 87 The LMBD protein is encoded by the gene LMBRD1 [limb region 1 (LMBR1) domain containing 1 gene (lmbrd1)]; 88 it is involved in the conversion of vitamin B12 (also known as cobalamin) into one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). 89 adenosylcobalamin is required for the normal function of an enzyme known as methylmalonyl-CoA mutase.…”

LMBD1 protein participates in cell mitosis by regulating microtubule assembly

“…The increase of glucose uptake is a consequence of constitutive activation of IR signaling pathway resulting from the retention of IR on the plasma membrane [8]. Furthermore, LMBD1 function is essential for the expression of fibroblast growth factor 8 to provide intact gastrulation and mesoderm formation during mouse embryogenesis [9].…”