Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia

Adult-onset type II citrullinemia (CTLN2) is characterized by a liver-speci fic deficiency of argininosuccinate synthetase (ASS) protein. We have recen tly identified the gene responsible for CTLN2, viz., SLC25A13, which encode s a calcium-binding mitochondrial carrier protein, designated citrin, and f ound five mutations of the SLC25A13 gene in CTLN2 patients. In the present study, we have identified two novel mutations, 1800ins1 and R605X, in SLC25 A13 mRNA and the SLC25A13 gene. Diagnostic analysis for the seven mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies has r evealed that 102 patients had one or two of the seven mutations and 93 pati ents were homozygotes or compound heterozygotes. These results indicate tha t CTLN2 is caused by an abnormality in the SLC25A13 gene, and that our crit eria for CTLN2 before DNA diagnosis are correct. Five of 22 patients from c onsanguineous unions have been shown to be compound heterozygotes, suggesti ng a high frequency of the mutated genes. The frequency of homozygotes is c alculated to be more than 1 in 20,000 from carrier detection (6 in 400 indi viduals tested) in the Japanese population. We have detected no cross-react ive immune materials in the liver of CTLN2 patients with any of the seven m utations by Western blot analysis with anti-human citrin antibody. From the se findings, we hypothesize that CTLN2 is caused by a complete deletion of citrin, although the mechanism of ASS deficiency is still unknown.