Citrin Deficiency: A Defect in the Urea Cycle

Sir John E. Walker; Moderator: Wolfgang Lubitz

Category: Agora Talks

Date: 26 June 2023

Quality: HD MD SD

Citrin Deficiency: A Defect in the Urea Cycle (2023) - Sir John E. Walker; Moderator: Wolfgang Lubitz


The human SLC25A family of transporter proteins has 53 members, with 51 of them confined to the inner membranes of mitochondria. Perhaps the best-known members of the family are the ATP-ADP carrier, which exchanges internal ATP for external ADP, and the uncoupling protein involved in heat generation from the mitochondria in brown adipose tissue. All family members have common structural and functional features. They transport not only nucleotides, but also various metabolites and cofactors across the inner membrane of the organelle. Citrin, a member of this family, is responsible for the symport of glutamate along with a proton into the mitochondrial matrix and the export of aspartate from the matrix to the cytoplasm. As such, it is a key component of the malate/aspartate shuttle, controlling gluconeogenesis, amino acid and nucleotide metabolism, and involved in the disposal of ammonia arising from amino acid metabolism via the urea cycle. Citrin deficiency is a pan-ethnic disease arising from mutations in the SLC25A13 gene, which encodes the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2). In Japan, where the condition was first identified, the incidence has been estimated to be 1 in 17000. It is an autosomal recessive monogenic disease with a complex phenotype, including two major manifestations, the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the more severe adult-onset citrullinemia type II (CTLN2). A characteristic feature of the condition is the diversity of phenotypes between patients. Some patients recovering from NICCD go through a phase with mild clinical symptoms, mostly featuring strong food preferences, others suffer from failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). The aims of current research in this area, largely funded by the Citrin Foundation in Singapore, are to understand the molecular basis of the disease, to find ameliorating treatments, and ultimately a cure.