Imerslund-Gräsbeck syndrome is a condition caused by low levels of vitamin B12 (also known as cobalamin). The primary feature of this condition is a blood disorder called megaloblastic anemia. In this form of anemia, which is a disorder characterized by the shortage of red blood cells, the red cells that are present are abnormally large. About half of people with Imerslund-Gräsbeck syndrome also have high levels of protein in their urine (proteinuria). Although proteinuria can be an indication of kidney problems, people with Imerslund-Gräsbeck syndrome appear to have normal kidney function.

Imerslund-Gräsbeck syndrome typically begins in infancy or early childhood. The blood abnormality leads to many of the signs and symptoms of the condition, including an inability to grow and gain weight at the expected rate (failure to thrive), pale skin (pallor), excessive tiredness (fatigue), and recurring gastrointestinal or respiratory infections. Other features of Imerslund-Gräsbeck syndrome include mild neurological problems, such as weak muscle tone (hypotonia), numbness or tingling in the hands or feet, movement problems, delayed development, or confusion. Rarely, affected individuals have abnormalities of organs or tissues that make up the urinary tract, such as the bladder or the tubes that carry fluid from the kidneys to the bladder (the ureters).

Mutations in the AMN or CUBN gene can cause Imerslund-Gräsbeck syndrome. The AMN gene provides instructions for making a protein called amnionless, and the CUBN gene provides instructions for making a protein called cubilin. Together, these proteins play a role in the uptake of vitamin B12 from food. Vitamin B12, which cannot be made in the body and can only be obtained from food, is essential for the formation of DNA and proteins, the production of cellular energy, and the breakdown of fats. This vitamin is involved in the formation of red blood cells and maintenance of the brain and spinal cord (central nervous system).

The amnionless protein is embedded primarily in the membrane of kidney cells and cells that line the small intestine. Amnionless attaches (binds) to cubilin, anchoring cubilin to the cell membrane. Cubilin can interact with molecules and proteins passing through the intestine or kidneys. During digestion, vitamin B12 is released from food. As the vitamin passes through the small intestine, cubilin binds to it. Amnionless helps transfer the cubilin-vitamin B12 complex into the intestinal cell. From there, the vitamin is released into the blood and transported throughout the body. In the kidney, the amnionless and cubilin proteins are involved in the reabsorption of certain proteins that would otherwise be released in urine.

Mutations in the AMN gene prevent cubilin from attaching to the cells in the small intestine and kidneys. Without cubilin function in the small intestine, vitamin B12 is not taken into the body. A shortage of this essential vitamin impairs the proper development of red blood cells, leading to megaloblastic anemia. Low levels of vitamin B12 can also affect the central nervous system, causing neurological problems. In addition, without cubilin function in the kidneys, proteins are not reabsorbed and are instead released in urine, leading to proteinuria.

Like AMN gene mutations, some CUBN gene mutations impair cubilin's function in both the small intestine and the kidneys, leading to a shortage of vitamin B12 and proteinuria. Other CUBN gene mutations affect cubilin's function only in the small intestine, impairing uptake of vitamin B12 into the intestinal cells. Individuals with these mutations have a shortage of vitamin B12, which can lead to megaloblastic anemia and neurological problems, but not proteinuria.

Normal Function

The AMN gene provides instructions for making a protein called amnionless. This protein is involved in the uptake of vitamin B12 (also called cobalamin) from food. Vitamin B12, which cannot be made in the body and can only be obtained from food, is essential for the formation of DNA and proteins, the production of cellular energy, and the breakdown of fats. This vitamin is involved in the formation of red blood cells and maintenance of the brain and spinal cord (central nervous system).

The amnionless protein is primarily found embedded in the outer membrane of kidney cells and cells that line the small intestine. Amnionless attaches (binds) to another protein called cubilin, anchoring cubilin to the cell membrane. Cubilin can interact with molecules and proteins passing through the intestine or kidneys. During digestion, vitamin B12 is released from food. As the vitamin passes through the small intestine, cubilin binds to it. Amnionless helps transfer the cubilin-vitamin B12 complex into the intestinal cell. From there, the vitamin is released into the blood and transported throughout the body. In the kidneys, amnionless and cubilin are involved in the reabsorption of certain proteins that would otherwise be released in urine.

Health Conditions Related to Genetic Changes

Imerslund-Gräsbeck syndrome

At least 30 mutations in the AMN gene have been found to cause 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.

AMN gene mutations that cause Imerslund-Gräsbeck syndrome reduce the amount or function of the amnionless protein. Without amnionless acting as an anchor, cubilin is not attached to cells in the small intestine or kidneys and cannot bind to vitamin B12 and other molecules and proteins needed in the body. As a result, instead of being taken into intestinal cells, vitamin B12 is released from the body. A shortage of this essential vitamin impairs the proper development of red blood cells, leading to megaloblastic anemia. Low levels of vitamin B12 can also affect the central nervous system, causing neurological problems. In addition, without amnionless function in the kidneys, proteins are not reabsorbed into the body and are instead released in the urine, leading to proteinuria.

Other Names for This Gene

• amnionless
• amnionless homolog
• PRO1028
• protein amnionless
• protein amnionless precursor
• visceral endoderm-specific type 1 transmembrane protein

Genomic Location

Normal Function

The CUBN gene provides instructions for making a protein called cubilin. This protein is involved in the uptake of vitamin B12 (also called cobalamin) from food into the body. Vitamin B12, which cannot be made in the body and can only be obtained from food, is essential for the formation of DNA and proteins, the production of cellular energy, and the breakdown of fats. This vitamin is involved in the formation of red blood cells and maintenance of the brain and spinal cord (central nervous system).

The cubilin protein is primarily found associated with kidney cells and cells that line the small intestine. Cubilin is anchored to the outer membrane of these cells by its attachment to another protein called amnionless. Cubilin can interact with molecules and proteins passing through the small intestine and kidneys, including vitamin B12. During digestion, vitamin B12 is released from food. As the vitamin passes through the small intestine, cubilin attaches (binds) to it. Amnionless helps transfer the cubilin-vitamin B12 complex into the intestinal cell. From there, the vitamin is released into the blood and transported throughout the body. In the kidneys, cubilin and amnionless are involved in the reabsorption of certain proteins that would otherwise be released in urine.

Health Conditions Related to Genetic Changes

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.

Other Names for This Gene

• 460 kDa receptor
• cubilin (intrinsic factor-cobalamin receptor)
• cubilin precursor
• gp280
• IFCR
• intestinal intrinsic factor receptor
• intrinsic factor-vitamin B12 receptor
• MGA1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Imerslund-Gräsbeck syndrome is a rare condition that was first described in Finland and Norway; in these regions, the condition is estimated to affect 1 in 200,000 people. The condition has also been reported in other countries worldwide; its prevalence in these countries is unknown.