Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

Abstract

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) Abstract By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2.Received

AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate

“…AGC1 is an important component of the neuronal malate/aspartate shuttle (Palmieri 2004), which is a crucial system to export intramitochondrial aspartate and to transfer the reducing equivalents of NADH from cytosol to mitochondria and hence to support oxidative phosphorylation (Lasorsa et al 2003). A distinct disorder, AGC2 deficiency, results from SLC25A13 mutations that reduce aspartate-glutamate carrier isoform 2 (AGC2) function with impaired malate/aspartate shuttle activity in the liver (Saheki and Kobayashi 2002). The prior report in the Swedish infant demonstrated complete loss of recombinant mutant AGC1 activity, resulting in no transport of aspartate or glutamate even after a 60 min incubation period (Wibom et al 2009).…”

Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

“…Although aralar deficiency is not known, citrin deficiency, an autosomal recessive disorder, causes not only CTLN2 in adults Yasuda et al 2000) but also idiopathic neonatal hepatitis associated with jaundice in neonates/infantiles Tazawa et al 2001;Tomomasa et al 2001). As the symptoms in the neonates were different from those found in CTLN2, the neonatal disease was named neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD; MIM#605814) Saheki and Kobayashi 2002).…”

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

“…It should be noted that some NICCD patients develop CTLN2 at their twenties or even several decades later (7, 8). Although the prognosis of CTLN2 is poor, liver transplantation is remarkably effective (3). As yet, it cannot be determined which NICCD patients will later develop CTLN2, and thus, all NICCD patients should be followed for signs of development of CTLN2.…”