Transcobalamin I (TC I) deficiency, a common cause of falsely low serum cobalamin (Cbl), is usually genetic, and plasma corrinoid analogs are decreased: is “withholding” Cbl and its analogs from human cells and the microbiome the chief biological role for TC I?

AbstractIn mammals, a subset of arginine tRNA isoacceptors are methylated in the anticodon loop by the METTL2 methyltransferase to form the 3-methylcytosine (m3C) modification. However, the mechanism by which METTL2 identifies specific arginine tRNAs for m3C formation as well as the biological role of m3C in mammals is unknown. Here, we show that human METTL2 forms a complex with DALR anticodon binding domain containing 3 (DALRD3) protein in order to recognize particular arginine tRNAs destined for m3C modification. Using biochemical reconstitution, we find that METTL2-DALDR3 complexes catalyze m3C formation in vitro that is dependent upon sequence elements specific to certain arginine tRNAs. Notably, DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in arginine tRNAs. These findings uncover an unexpected function for the DALRD3 protein in the targeting of distinct arginine tRNAs for m3C modification.

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Congenital transcobalamin II deficiency presenting atypically with a low serum cobalamin level: studies demonstrating the coexistence of a circulating transcobalamin I (R binder) complex

Blood ◽

10.1182/blood.v63.3.598.598 ◽

1984 ◽

Vol 63 (3) ◽

pp. 598-605 ◽

Cited By ~ 15

Author(s):

R Carmel ◽

Y Ravindranath

Keyword(s):

Differential Diagnosis ◽

Clinical Presentation ◽

Binding Protein ◽

Biochemical Feature ◽

Neurologic Dysfunction ◽

Low Serum ◽

Transcobalamin I ◽

Transcobalamin Ii

Abstract A case of transcobalamin II deficiency with several unique features is described. The clinical presentation was typical, except for a slightly delayed age at presentation and the occurrence of apparent neurologic dysfunction from the beginning. The unusual biochemical feature was a low serum cobalamin level (97 pg/ml). Several cobalamin-binding protein abnormalities coexisted and antedated cobalamin therapy. Chief among these was the complexing of all serum R binder (transcobalamin I), leaving the patient with no detectable R binder. This defect appeared to be transient. Noteworthy, too, was a prominent binder of 70,000 mol wt that also carried the bulk of his serum cobalamin after therapy; it was prominent in his presumably heterozygous relatives too. The interrelationship between all these abnormalities is intriguing but unclear. The abnormality in transcobalamin II deficiency is clearly not limited solely to deficiency of transcobalamin II. It is also evident that this entity must now be considered in the differential diagnosis of low serum cobalamin levels in infancy.

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Mild Transcobalamin I (Haptocorrin) Deficiency and Low Serum Cobalamin Concentrations

Clinical Chemistry ◽

10.1373/49.8.1367 ◽

2003 ◽

Vol 49 (8) ◽

pp. 1367-1374 ◽

Cited By ~ 56

Author(s):

Ralph Carmel

Keyword(s):

Healthy Volunteers ◽

Reference Interval ◽

Heterozygous State ◽

Plasma Samples ◽

Biochemical Phenotype ◽

Metabolic Evaluation ◽

Clinical Laboratories ◽

Mild Deficiency ◽

Low Serum ◽

Transcobalamin I

Abstract Background: Low cobalamin concentrations are common, but their causes are often unknown. Transcobalamin I/haptocorrin (TC I/HC) deficiency, viewed as a rare cause, has not been examined systematically in patients with unexplained low serum cobalamin. Methods: Total TC I/HC was measured by RIA in three subgroups of 367, 160, and 38 patients with different categories of low cobalamin concentrations and three comparison subgroups of 112, 281, and 119 individuals with cobalamin concentrations within the reference interval. Additional studies, including family studies, were done in selected patients found to have low TC I/HC concentrations. Results: Low TC I/HC concentrations suggestive of mild TC I/HC deficiency occurred in 54 of 367 (15%) patients with low cobalamin identified by clinical laboratories and 24 of 160 (15%) patients whose low cobalamin was unexplained after absorption and metabolic evaluation, but in only 2 of 38 patients with malabsorptive causes of low cobalamin concentrations (5%). The prevalence was only 3% (8 of 281 plasma samples) to 5% (6 of 112 sera) in patients with cobalamin concentrations within the reference interval and 3% (4 of 119) in healthy volunteers. Three patients with low cobalamin (0.6%) had severe TC I/HC deficiency with undetectable TC I/HC. Presumptive heterozygotes for severe TC I/HC deficiency in two families had the findings of mild TC I/HC deficiency; mild deficiency was also found in at least three of seven studied families of patients with mild TC I/HC deficiency. Conclusions: Mild TC I/HC deficiency is frequently associated with low cobalamin, is often familial, and its biochemical phenotype appears identical to the heterozygous state of severe TC I/HC deficiency. Severe TC I/HC deficiency also appears to be more common than suspected. Both diagnoses should be considered in all patients with unexplained low serum cobalamin.

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Deletion of the lactoperoxidase gene causes multisystem inflammation and tumors in mice

Scientific Reports ◽

10.1038/s41598-021-91745-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jayden Yamakaze ◽

Zhe Lu

Keyword(s):

Redox Reaction ◽

Human Cells ◽

Mutant Mice ◽

Biological Role ◽

Protective Mechanism ◽

Enzymatic Mechanism ◽

High Incidence ◽

Cultured Human Cells

AbstractStrongly oxidative H2O2 is biologically important, but if uncontrolled, would lead to tissue injuries. Lactoperoxidase (LPO) catalyzes the redox reaction of reducing highly reactive H2O2 to H2O while oxidizing thiocyanate (SCN−) to relatively tissue-innocuous hypothiocyanite (OSCN−). SCN− is the only known natural, effective reducing-substrate of LPO; humans normally derive SCN− solely from food. While its enzymatic mechanism is understood, the actual biological role of the LPO-SCN− system in mammals remains unestablished. Our group previously showed that this system protected cultured human cells from H2O2-caused injuries, a basis for the hypothesis that general deficiency of such an antioxidative mechanism would lead to multisystem inflammation and tumors. To test this hypothesis, we globally deleted the Lpo gene in mice. The mutant mice exhibited inflammation and lesions in the cardiovascular, respiratory, digestive or excretory systems, neuropathology, and tumors, with high incidence. Thus, this understudied LPO-SCN− system is an essential protective mechanism in vivo.

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Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels

British Journal of Haematology ◽

10.1111/j.1365-2141.2009.07855.x ◽

2009 ◽

Vol 147 (3) ◽

pp. 386-391 ◽

Cited By ~ 19

Author(s):

Ralph Carmel ◽

James Parker ◽

Zvi Kelman

Keyword(s):

Low Serum ◽

Transcobalamin I

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Congenital transcobalamin II deficiency presenting atypically with a low serum cobalamin level: studies demonstrating the coexistence of a circulating transcobalamin I (R binder) complex

Blood ◽

10.1182/blood.v63.3.598.bloodjournal633598 ◽

1984 ◽

Vol 63 (3) ◽

pp. 598-605

Author(s):

R Carmel ◽

Y Ravindranath

Keyword(s):

Differential Diagnosis ◽

Clinical Presentation ◽

Binding Protein ◽

Biochemical Feature ◽

Neurologic Dysfunction ◽

Low Serum ◽

Transcobalamin I ◽

Transcobalamin Ii

A case of transcobalamin II deficiency with several unique features is described. The clinical presentation was typical, except for a slightly delayed age at presentation and the occurrence of apparent neurologic dysfunction from the beginning. The unusual biochemical feature was a low serum cobalamin level (97 pg/ml). Several cobalamin-binding protein abnormalities coexisted and antedated cobalamin therapy. Chief among these was the complexing of all serum R binder (transcobalamin I), leaving the patient with no detectable R binder. This defect appeared to be transient. Noteworthy, too, was a prominent binder of 70,000 mol wt that also carried the bulk of his serum cobalamin after therapy; it was prominent in his presumably heterozygous relatives too. The interrelationship between all these abnormalities is intriguing but unclear. The abnormality in transcobalamin II deficiency is clearly not limited solely to deficiency of transcobalamin II. It is also evident that this entity must now be considered in the differential diagnosis of low serum cobalamin levels in infancy.

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Fibronexus-Like Adhesion Sites are Present at the Invasive Zones of Human Epidermoid Carcinomas

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053280 ◽

1982 ◽

Vol 40 ◽

pp. 106-109

Author(s):

Irwin I. Singer

Keyword(s):

Cell Cycle ◽

Serum Concentration ◽

Substrate Binding ◽

High Serum ◽

Adhesion Sites ◽

Substrate Adhesion ◽

Focal Contacts ◽

Adhesion Complex ◽

Low Serum

Our previous results indicate that two types of fibronectin-cytoskeletal associations may be formed at the fibroblast surface: dorsal matrixbinding fibronexuses generated in high serum (5% FBS) cultures, and ventral substrate-adhering units formed in low serum (0.3% FBS) cultures. The substrate-adhering fibronexus consists of at least vinculin (VN) and actin in its cytoplasmic leg, and fibronectin (FN) as one of its major extracellular components. This substrate-adhesion complex is localized in focal contacts, the sites of closest substratum approach visualized with interference reflection microscopy, which appear to be the major points of cell-tosubstrate adhesion. In fibroblasts, the latter substrate-binding complex is characteristic of cultures that are arrested at the G1 phase of the cell cycle due to the low serum concentration in their medium. These arrested fibroblasts are very well spread, flattened, and immobile.

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