SLC25A13

The SLC25A13 gene provides instructions for making a protein called citrin. This protein is active chiefly in the liver, kidneys, and heart. Within the cells of these organs, citrin is involved in transporting molecules into and out of energy-producing structures called mitochondria. Specifically, citrin carries a protein building block (amino acid) called glutamate into mitochondria and transports the amino acid aspartate out of mitochondria as part of a process called the malate-aspartate shuttle.

An adequate supply of aspartate must be transported out of mitochondria to participate in a process called the urea cycle. The urea cycle is a sequence of chemical reactions that takes place in liver cells. These reactions process excess nitrogen that is generated as the body uses proteins. The excess nitrogen is used to make a compound called urea, which is excreted from the body in urine.

Citrin participates in several other important cellular functions as part of the malate-aspartate shuttle. This protein plays a role in producing and breaking down simple sugars and making proteins. It is also involved in the production of nucleotides, which are the building blocks of DNA and its chemical cousin, RNA.

citrullinemia - caused by mutations in the SLC25A13 gene

More than 20 mutations in the SLC25A13 gene have been identified in people with adult-onset type II citrullinemia. Almost all of the identified mutations lead to the production of an unstable citrin protein that is quickly broken down or an abnormally short, nonfunctional version of the protein.

A lack of functional citrin blocks the malate-aspartate shuttle, including the transport of aspartate out of mitochondria. This loss of citrin inhibits the normal production of proteins and nucleotides. It also reduces the amount of aspartate available to take part in the urea cycle. As a result, the liver cannot effectively process excess nitrogen into urea. A disruption in the urea cycle allows nitrogen (in the form of ammonia) and other byproducts of the urea cycle (such as citrulline) to build up in the bloodstream. Ammonia is toxic, especially to the nervous system, which helps explain the development of abnormal behaviors and other neurologic problems in people with adult-onset type II citrullinemia.

Mutations in the SLC25A13 gene also have been found in infants with a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver disorder is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. Ammonia does not build up in the bloodstream of infants with NICCD, and the signs and symptoms typically resolve within a year. Many infants with NICCD have the same mutations in the SLC25A13 gene as people with adult-onset type II citrullinemia. Years or even decades later, some people who had NICCD as infants develop the characteristic features of adult-onset type II citrullinemia.