2.1 Imerslund-Gräsbeck Syndrome

At least 35 mutations in the CUBN gene have been found to cause a condition called Imerslund-Gräsbeck syndrome. This condition is characterized by low levels of vitamin B12 in the body, which leads to a blood disorder known as megaloblastic anemia. About half of affected individuals also have excess protein in their urine (proteinuria), and some have neurological problems.

The most common CUBN gene mutation, which is found in people of Finnish heritage, changes a single protein building block (amino acid) in the cubilin protein; the amino acid proline is replaced by the amino acid leucine at position 1297 (written as Pro1297Leu or P1297L). The protein alteration impairs cubilin's ability to bind to vitamin B12. Instead of being taken up into intestinal cells, the vitamin is released from the body. A shortage of this essential vitamin impairs the proper development of red blood cells, leading to megaloblastic anemia. In addition, low levels of vitamin B12 can affect the central nervous system, causing neurological problems.

Other CUBN gene mutations prevent cubilin from attaching to the amnionless protein or lead to a reduction in the amount or function of the cubilin protein. These changes impair cubilin's function in the kidneys as well as in the small intestine. Without amnionless function in the kidneys, proteins are not reabsorbed into the body and are instead released in the urine, leading to proteinuria. Individuals with these mutations develop megaloblastic anemia and proteinuria.