Genetic basis of Cobalamin Malabsorption Cubilin Deficiency (Border Collie Type) - is an autosomal recessive inherited disorder caused by a mutation in the CUBN gene, which encodes the protein cubilin. Cubilin is essential for the intestinal absorption and renal reabsorption of certain nutrients, particularly vitamin B12 (cobalamin). Dogs must inherit two copies of the pathogenic CUBN mutation—one from each parent—to develop the disease. Carriers with one copy are clinically normal but can pass the mutation to offspring. This condition is recognised in Border Collies, with genetic testing available to identify carriers and affected dogs for informed breeding decisions.
Pathophysiology - Cubilin plays a critical role in binding the intrinsic factor–cobalamin complex in the small intestine and enabling its absorption into the body. In affected Border Collies, the CUBN gene mutation results in deficient or nonfunctional cubilin, preventing normal intestinal absorption of cobalamin and renal reabsorption of specific proteins. This leads to Cobalamin deficiency with secondary metabolic disruption, evidenced by elevated methylmalonic acid levels in urine from as early as 14 weeks of age. Progressive metabolic and haematological abnormalities affecting energy metabolism, protein metabolism, and blood cell formation. Proteinuria (loss of certain proteins into urine) due to impaired tubular reabsorption in the kidney.
Complications - Clinical signs may not appear until months or years after biochemical abnormalities are detectable. When present, signs include General symptoms: Anorexia, lethargy, poor weight gain, and reduced muscle mass. Haematologic abnormalities: Anemia and reduced numbers of neutrophils (neutropenia) due to impaired blood cell production. Neurological complication (rare but severe): Hepatic encephalopathy, which can cause altered mental status, seizures, coma, and death. Persistent proteinuria: Even with vitamin B12 supplementation and resolution of clinical signs, affected dogs continue to have increased urinary excretion of certain proteins throughout life. Without supplementation, the disease is progressive and can result in severe metabolic compromise and death.
Why This Matters to Breeders and Vets
Breeding control: As an autosomal recessive disease, breeding two carriers will produce, on average, 25% affected puppies. Genetic testing for the CUBN mutation allows breeders to avoid high-risk pairings while still maintaining genetic diversity in the Border Collie population.
Early detection: Elevated urinary methylmalonic acid may be detectable well before clinical signs, enabling early diagnosis and intervention in at-risk dogs.
Management: Affected dogs require lifelong cobalamin supplementation, which results in remission of most clinical signs within weeks of initiation. This treatment is inexpensive and effective, making early diagnosis critical to a good outcome.
Veterinary role: Vets should consider this diagnosis in Border Collies with unexplained weight loss, lethargy, anemia, or neurological signs, particularly if accompanied by proteinuria.
Summary - Cobalamin Malabsorption: Cubilin Deficiency (Border Collie Type) is an autosomal recessive disorder caused by mutations in the CUBN gene. It results in defective absorption of vitamin B12 and increased urinary protein loss. While biochemical changes can be detected from 14 weeks of age, clinical signs such as anorexia, lethargy, poor growth, muscle loss, anemia, and—in rare cases—hepatic encephalopathy may not appear for months or years. Lifelong vitamin B12 supplementation leads to remission of signs in most dogs, although proteinuria persists. Genetic testing is essential for controlling this disease in the Border Collie breed and enables early veterinary intervention.