intrinsic-factor and Proteinuria

In our pioneering work in 1956, two binders of vitamin B12 (B12) alias cobalamin (Cbl) were identified in gastric juice, S with slow electrophoretic mobility, a 70 kD protein with intrinsic factor (IF) activity and another rapid (R), not IF active but probable digestion product. Numerous sources contained a protein immunologically identical to R (haptocorrin, Hc). Another IF-active component (I) was found. Isoelectric focusing showed that S, I and R were assemblies of "isoproteins" with different pI's due to varying glycosidation. Isolation of S, I and R in microquantities was achieved in 1962 using a series of ion exchange chromatographies and gel filtration. Ponderable products were obtained in 1965-1966. The B12-IF complex was a dimer, contained 13% carbohydrate and showed a different absorption spectrum than B12. Using the Schilling test, B12 absorption was shown to require Ca(++), bound in vitro to the ileal receptor and IF, but most of Ca(++) could be removed with sialidase. The receptor-substrate complex contained Ca(++) and carbohydrate. The purified receptor was shown to contain two main subunits. The Imerslund-Gräsbeck syndrome was discovered 1958-1960; it is caused by mutations in either of two genes, cubilin or amnionless, which form the multiligand receptor cubam. Testicular biopsies during and after B12-treated deficiency showed remarkable improvement after therapy. Studies of the turnover of radioactive B12 revealed biliary and fecal excretion, enterohepatic circulation and allowed calculation of biological half-life and daily need. The B12 coenzymes largely behaved like B12. To study whether radiocobalt in B12 was representative of the rest of the B12 molecule, (32)P and (57)Co labeled hydroxocobalamins were biosynthesized and shown to behave identically when given simultaneously to rats. The complex metabolism of B12 explains the pathogenesis of B12 deficiencies. Some of its mechanisms are not restricted to B12, e.g. the endocytosis of B12-IF also applies to other macromolecules.

Topics: Anemia, Megaloblastic; Animals; Gastric Juice; Humans; Intrinsic Factor; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

The disease is characterised by cobalamin (Cbl) deficiency in children 0-5 years old, causing failure to thrive, infections, megaloblastic anaemia, neuropathy, and mild general malabsorption; slight proteinuria is common. Cbl injections produce remission, but Cbl malabsorption and proteinuria persist. About 250 cases have been reported. Dogs also have it. The heredity is autosomal and recessive. The physiological and pathological absorption mechanisms are described: Cbl liberated from food by digestion is first bound to haptocorrin, but in the intestine it is transferred to intrinsic factor. In the ileum the complex attaches to a receptor on the enterocytes; this requires neutral pH and Ca2+. The receptor is a membrane-bound glycoprotein consisting of multiple subunits. The receptor-ligand complex is endocytosed and degraded in lysosomes, and the vitamin is transferred to transcobalamin which carries it to tissues. The same receptor is strongly expressed in the kidneys, but urine also contains its activity which can be assayed for diagnosis. The basic lesion is an error in the ileal receptor. In the affected dogs the synthesised receptor is retained intracellularly. Urine and ileal biopsies from human cases contained little receptor but it had conserved affinity for the ligand. Recently examined Arab patients did not excrete reduced amounts of the receptor. Apparently, the disease has subsets, such as different structural errors in the receptor and possibly faulty transport inside the enterocyte. The cause of the proteinuria is unknown but kidney damage due to severe Cbl deficiency and an error in a multiligand renal receptor are among the possibilities.

Topics: Animals; Child, Preschool; Dogs; Genes, Recessive; Humans; Infant; Infant, Newborn; Intrinsic Factor; Malabsorption Syndromes; Proteinuria; Receptors, Cell Surface; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Antigens; Bence Jones Protein; Blood Proteins; Brain Chemistry; Cerebrospinal Fluid Proteins; Electrophoresis, Polyacrylamide Gel; Enzymes; Hormones; Humans; Immunoelectrophoresis; Interferons; Intrinsic Factor; Isoelectric Focusing; Liver; Metabolism, Inborn Errors; Muscle Proteins; Phosphoric Monoester Hydrolases; Proteinuria; Pyrogens; Saliva; Tissue Extracts

Topics: Anemia, Macrocytic; Anemia, Pernicious; Child; Child, Preschool; Diphyllobothriasis; Female; Folic Acid Deficiency; Humans; Infant; Infant Nutrition Disorders; Infant, Newborn; Intrinsic Factor; Kwashiorkor; Malabsorption Syndromes; Male; Proteinuria; Thiamine; Transferases; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Anemia, Pernicious; Child, Preschool; Gastric Mucosa; Humans; Ileum; Infant; Infant, Newborn; Intestinal Mucosa; Intrinsic Factor; Kidney; Malabsorption Syndromes; Proteinuria; Urogenital Abnormalities; Vitamin B 12

Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult.. We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12  years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients.. Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved.. Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype.

Topics: Anemia, Megaloblastic; Ethnicity; Female; Founder Effect; Genetic Association Studies; Genetic Heterogeneity; Genetic Testing; Humans; Intrinsic Factor; Malabsorption Syndromes; Male; Membrane Proteins; Mutation; Proteins; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Cubilin is a high molecular weight multiligand receptor that mediates intestinal absorption of intrinsic factor-cobalamin and selective protein reabsorption in renal tubules. The genetic basis of selective intestinal cobalamin malabsorption with proteinuria was investigated in a canine model closely resembling human Imerslund-Gräsbeck syndrome caused by cubilin mutations. Canine CUBN cDNA was cloned and sequenced, showing high identity with human and rat CUBN cDNAs. An intragenic CUBN marker was identified in the canine family and used to test the hypothesis of genetic linkage of the disease and CUBN loci. Linkage was rejected, indicating that the canine disorder resembling Imerslund-Gräsbeck syndrome is caused by defect of a gene product other than cubilin. These results imply that there may be locus heterogeneity among human kindreds with selective intestinal cobalamin malabsorption and proteinuria and that normal brush-border expression of cubilin requires the activity of an accessory protein.

Topics: Amino Acid Sequence; Animals; DNA, Complementary; Dogs; Female; Genetic Predisposition to Disease; Humans; Intestinal Absorption; Intrinsic Factor; Male; Microvilli; Molecular Sequence Data; Proteinuria; Receptors, Cell Surface; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Follow-Up Studies; Humans; Intestinal Absorption; Intrinsic Factor; Lymphangiectasis, Intestinal; Malabsorption Syndromes; Male; Protein-Losing Enteropathies; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Agammaglobulinemia; Anemia, Macrocytic; Anemia, Megaloblastic; Antibody Formation; Chronic Disease; Female; Gastric Juice; Humans; Immunoglobulin A; Immunoglobulin G; Immunologic Deficiency Syndromes; Intrinsic Factor; Malabsorption Syndromes; Male; Proteinuria; Syndrome; Vitamin B 12 Deficiency

Topics: Alkaline Phosphatase; Bile; Blood Proteins; Carcinoma; Cerebrospinal Fluid Proteins; Chemistry, Clinical; Gastric Juice; Humans; Immunoglobulins; Intrinsic Factor; Isoelectric Focusing; Isoenzymes; Kidney Cortex; Kidney Medulla; Kidney Neoplasms; Methods; Multiple Sclerosis; Nephrotic Syndrome; Nerve Tissue Proteins; Proteinuria; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Humans; Immunologic Deficiency Syndromes; Intrinsic Factor; Malabsorption Syndromes; Male; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Anemia, Pernicious; Binding Sites; Biopsy; Child; Gastric Juice; Humans; Ileum; Intestinal Absorption; Intestinal Mucosa; Intrinsic Factor; Malabsorption Syndromes; Male; Microscopy, Electron; Proteinuria; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Bone Marrow Examination; Female; Gastric Juice; Humans; Hydrochloric Acid; Infant; Intrinsic Factor; Kidney Function Tests; Malabsorption Syndromes; Male; Proteinuria; Schilling Test; Vitamin B 12

Topics: Adult; Anemia, Pernicious; Autoantibodies; Biological Assay; Gastric Juice; Humans; Intestinal Absorption; Intrinsic Factor; Male; Proteinuria; Schilling Test; Vitamin B 12

Topics: Adult; Anemia, Pernicious; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Female; Humans; Ileum; Intestinal Absorption; Intrinsic Factor; Jejunum; Kidney; Male; Proteinuria; Urogenital Abnormalities; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Pernicious; Diagnosis, Differential; Humans; Intestinal Absorption; Intrinsic Factor; Metabolism; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency