Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor

Area of Science:

• Genetics and Molecular Biology
• Pediatric Gastroenterology
• Nutritional Science

Background:

• An inherited disorder characterized by cobalamin (Cbl) deficiency in young children (0-5 years) leads to failure to thrive, infections, megaloblastic anemia, and neuropathy.
• While Cbl injections provide remission, the underlying malabsorption and associated proteinuria persist, affecting approximately 250 reported cases, with a similar condition observed in dogs.
• The condition follows an autosomal recessive inheritance pattern.

Purpose of the Study:

• To elucidate the physiological and pathological mechanisms of cobalamin absorption.
• To identify the molecular basis of the inherited Cbl malabsorption disorder.
• To explore potential diagnostic markers and understand the etiology of associated proteinuria.

Main Methods:

• Detailed description of cobalamin (Cbl) absorption pathway involving haptocorrin, intrinsic factor, ileal receptor, and transcobalamin.
• Analysis of ileal receptor structure and function in affected individuals and canine models.
• Assay of ileal receptor activity in urine for diagnostic purposes.

Main Results:

• The primary defect lies in the ileal receptor responsible for Cbl absorption, a membrane-bound glycoprotein.
• In affected dogs, the synthesized receptor is retained intracellularly; human cases show reduced receptor levels in ileal biopsies but conserved ligand affinity.
• Recent findings suggest potential disease subsets with varying receptor structural errors or transport defects; proteinuria cause remains unclear.

Conclusions:

• The inherited cobalamin malabsorption disorder stems from a defect in the ileal Cbl receptor.
• The disease may present with distinct subsets, indicating complex genetic and molecular heterogeneity.
• Further research is needed to determine the cause of proteinuria and fully characterize the receptor defects.