Citrin

Calcium Binding to Citrin

Citrin is a protein that plays a crucial role in the metabolism of carbohydrates and amino acids. It is encoded by the SLC25A13 gene in humans and is a member of the solute carrier family 25 (SLC25), which transports substances across mitochondrial membranes. Citrin deficiency, resulting from mutations in the SLC25A13 gene, leads to a range of metabolic disorders, including Adult-onset type II citrullinemia (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD).

Function

Citrin acts as a mitochondrial aspartate-glutamate carrier, facilitating the exchange of aspartate for glutamate across the mitochondrial membrane. This exchange is critical for the urea cycle and the malate-aspartate shuttle, which are essential for detoxifying ammonia and transferring reducing equivalents, respectively. By doing so, citrin plays a vital role in energy production, especially in the liver, heart, and muscle tissue.

Clinical Significance

Citrin deficiency manifests in two major forms: NICCD and CTLN2. NICCD typically presents in infancy with symptoms such as cholestasis, failure to thrive, hypoglycemia, and galactosemia. Most NICCD symptoms resolve spontaneously by the age of one year. However, some individuals may later develop CTLN2, a more severe condition characterized by recurrent hyperammonemia, neuropsychiatric symptoms, and liver dysfunction in adulthood.

Genetics

The SLC25A13 gene mutations responsible for citrin deficiency are inherited in an autosomal recessive manner. This means that an individual must inherit two copies of the mutated gene, one from each parent, to be affected by the condition. Genetic testing can identify carriers of the mutation and help diagnose affected individuals.

Diagnosis and Treatment

Diagnosis of citrin deficiency involves biochemical tests that show abnormal levels of certain amino acids in the blood, such as elevated citrulline, and genetic testing for mutations in the SLC25A13 gene. Treatment focuses on managing symptoms and may include dietary modifications, such as limiting carbohydrates and increasing protein intake, to prevent hyperammonemia episodes. In severe cases, especially in those with CTLN2, liver transplantation may be considered.

Research Directions

Research on citrin and its deficiency is ongoing, with studies aimed at understanding the precise mechanisms by which the mutations cause disease, developing more effective treatments, and exploring the role of citrin in other metabolic pathways and diseases.

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