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Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin
J C Fyfe1, K S Ramanujam, K Ramaswamy
1Section of Medical Genetics, Veterinary School, University of Pennsylvania, Philadelphia 19104-6010.
Insights
Cobalamin malabsorption in dogs is linked to a mutation in the intrinsic factor-cobalamin receptor (IFCR). This mutation causes inefficient expression of IFCR in the brush-border membrane, leading to impaired vitamin B12 absorption.
Area of Science:
- Gastroenterology and Hepatology
- Genetics and Genomics
- Biochemistry
Background:
- Selective cobalamin malabsorption is an inherited disorder affecting vitamin B12 uptake.
- The intrinsic factor-cobalamin receptor (IFCR) plays a crucial role in intestinal cobalamin absorption.
Purpose of the Study:
- To investigate the molecular basis of selective cobalamin malabsorption in a canine family.
- To characterize the intrinsic factor-cobalamin receptor (IFCR) in affected dogs.
Main Methods:
- Assessing IFCR ligand binding activity in ileal and kidney homogenates and brush-border membranes (BBM).
- Utilizing immunoblots, affinity chromatography, amino acid analysis, and protease cleavage to analyze IFCR.
- Examining oligosaccharide sensitivity using peptide N-glycosidase F and endoglycosidase H.
Main Results:
- Affected dogs showed significantly higher IFCR activity in ileal homogenates but lower activity in kidney homogenates compared to normal dogs.
- IFCR recovery in BBM was markedly reduced in affected dogs, with no detectable cross-reactive material in immunoblots.
- Purified IFCR from affected dogs exhibited altered amino acid composition and peptide maps, with distinct oligosaccharide processing.
Conclusions:
- Cobalamin malabsorption in this canine family is attributed to a mutation in the IFCR gene.
- The mutation leads to inefficient expression and retention of IFCR in an early cellular compartment, impairing vitamin B12 absorption.
Abstract:
Ligand binding activity of intrinsic factor-cobalamin receptor (IFCR) was determined in homogenates and isolated brush-border membranes (BBM) of ileum and kidney from dogs exhibiting simple autosomal recessive inheritance of selective cobalamin malabsorption (Fyfe, J. C., Giger, U., Hall, C. A., Jezyk, P. F., Klumpp, S. A., Levine, J. S., and Patterson, D. F. (1991) Pediatr. Res. 29, 24-31). IFCR activity of affected dog ileal homogenates was 3-4-fold higher than normal whereas IFCR activity in affected dog kidney homogenates was one-tenth of normal. The recovery of IFCR activity in the BBM of ileum and renal cortex of affected dogs was 30- and 20-fold less than normal, respectively. The dissociation constant (Kd) for intrinsic factor-cobalamin was similar in BBM of both tissues and was the same in affected and normal dogs. In the affected dog ileal BBM, activities of alkaline phosphatase and sucrase-isomaltase and vesicular transport of glucose and Na(+)-taurocholate were normal. Immunoblots showed no IFCR cross-reactive material in the ileal or renal BBM of affected dogs. IFCR purified by affinity chromatography from kidney of both normal and affected dogs had an Mr = 230,000. However, amino acid analysis revealed that the affected dog IFCR had more lysine than the normal, and protease cleavage of the purified IFCRs revealed different peptide maps. Asparagine-linked oligosaccharides of both proteins were sensitive to peptide N-glycosidase F cleavage, but only the affected dog IFCR was endoglycosidase H sensitive. These results suggest that cobalamin malabsorption in this canine family is caused by inefficient BBM expression of IFCR due to a mutation of IFCR and its retention in an early biosynthetic compartment.
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