Deficiency of the specific granule proteins, R-binder/transcobalamin I and lactoferrin, in plasma and saliva: A new disorder

Lin, Judith C.; Borregaard, Niels; Liebman, Howard A.; Carmel, Ralph

doi:10.1002/ajmg.1232

Cited by 13 publications

(8 citation statements)

References 34 publications

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“…Furthermore, the up-regulation of lactoferrin, transcobalamin 1, and lipocalin 2 detected could also increase the protection against V. cholerae. All of these proteins are antibacterial proteins that are known to be secreted from granulated epithelial cells and neutrophils (4,10,15,22,23). Lactoferrin has been shown previously to have a strong bactericidal effect on V. cholerae (1), and this was confirmed in this study (data not shown).…”

Section: Resultssupporting

confidence: 86%

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

et al. 2007

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We used a whole-genome microarray screening system (Affymetrix human GeneChips covering 47,000 different transcripts) to examine the gene expression in duodenal mucosa during acute cholera. Biopsies were taken from the duodenal mucosa of seven cholera patients 2 and 30 days after the onset of diarrhea, and the gene expression patterns in the acute-and convalescent-phase samples were compared pairwise. Of about 21,000 transcripts expressed in the intestinal epithelium, 29 were defined as transcripts that were up-regulated and 33 were defined as transcripts that were down-regulated during acute cholera. The majority of the up-regulated genes characterized were found to have an established or possible role in the innate defense against infections; these genes included the LPLUNC1, LF, VCC1, TCN1, CD55, SERPINA3, MMP1, MMP3, IL1B, LCN2, SOCS3, GDF15, SLPI, CXCL13, and MUC1 genes. The results of confirmative PCR correlated well with the microarray data. An immunohistochemical analysis revealed increased expression of lactoferrin in lamina propria cells and increased expression of CD55 in epithelial cells, whereas increased expression of the SERPINA3 protein (␣ 1 -antichymotrypsin) was detected in both lamina propria and epithelial cells during acute cholera. The expression pattern of CD55 and SERPINA3 in cholera toxin (CT)-stimulated Caco-2 cells was the same as the pattern found in the intestinal mucosa during acute cholera, indicating that the activation of the CD55 and SERPINA3 genes in intestinal epithelium was induced by CT. In conclusion, during acute cholera infection, innate defense mechanisms are switched on to an extent not described previously. Both direct effects of CT on the epithelial cells and changes in the lamina propria cells contribute to this up-regulation.

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Section: Resultssupporting

confidence: 86%

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

et al. 2007

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“…With a frequency approximating 15% for a These are based in large part on the findings in families A and B in this report and other published (11)(12)(13)(14)(15)(16)28 ) and unpublished data on severe TC I/HC deficiency, and confirmed in patients identified in the surveys. mild TC I/HC deficiency and 0.6% for severe deficiency in patients with low cobalamin concentrations, TC I/HC deficiency may be exceeded in frequency as a cause of low cobalamin concentrations only by food-cobalamin malabsorption (6 ).…”

Section: Discussionmentioning

confidence: 52%

“…The unexplained discrepancy between the patterns found in blood and secretions suggests that TC I/HC is expressed, regulated, or elaborated differently in different cellular sources. The same kind of discrepancy between plasma and secretion concentrations in homozygotes and heterozygotes was evident for lactoferrin in family B, who had combined TC I/HC and lactoferrin deficiency (28 ).…”

Section: Discussionmentioning

confidence: 64%

“…TC I/HC deficiency does not appear to cause clinically recognizable cobalamin deficiency despite the low cobalamin concentrations. Neurologic problems have been described occasionally (11,28 ), but as illustrated in Table 2, they have atypical characteristics, do not respond to cobalamin therapy, and may be coincidental. Nevertheless, further study, including electrophysiologic testing, will be needed, especially in view of cases such as the father in family C, and the issue of neurologic associations remains open.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike family A, families B and C were identified before the surveys and helped prompt the undertaking of those surveys, as mentioned earlier. Family B provided the first view of presumptive heterozygosity for TC I/HC deficiency, albeit the precise deficiency in the two original propositi (11 ) was severe combined TC I/HC and lactoferrin deficiency (28 ). The presumptively heterozygous sons of the two propositi were found to have low but measurable plasma TC I/HC and cobalamin concentrations ( Table 1).…”

Section: Clinical Chemistry 49 No 8 2003mentioning

confidence: 99%

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

Carmel

2003

Clinical Chemistry

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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

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Inborn errors of cobalamin absorption and metabolism

Watkins

Rosenblatt²

2011

American J of Med Genetics Pt C

171

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Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

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Deficiency of the specific granule proteins, R-binder/transcobalamin I and lactoferrin, in plasma and saliva: A new disorder

Cited by 13 publications

References 34 publications

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

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

Inborn errors of cobalamin absorption and metabolism

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