The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein

Citrullinaemia (CTLN) is an autosomal recessive disease caused by deficienc y of argininosuccinate synthetase (ASS). Adultonset type II citrullinaemia (CTLN2) is characterized by a liverspecific ASS deficiency with no abnormal ities in hepatic ASS mRNA or the gene ASS (refs 1-17). CTLN2 patients (1/10 0.000 in Japan(13)) suffer from a disturbance of consciousness and coma, an d most die with cerebral edema within a few years of onset. CTLN2 differs f rom classical citrullinaemia (CTLN1, OMIM 215700) in that CTLN1 is neonatal or infantile in onset, with ASS enzyme defects (in all tissues) arising du e to mutations in ASS on chromosome 9q34 (refs 18-21). We collected 118 CTL N2 families, and localized the CTLN2 locus to chromosome 7q21.3 by homozygo sity mapping analysis of individuals from 18 consanguineous unions. Using p ositional cloning we identified a novel gene, SLC5A13, and found five diffe rent DNA sequence alterations that account for mutations in all consanguine ous patients examined. SLC25A13 encodes a 3.4-kb transcript expressed most abundantly in liver. The protein encoded by SLC25A13, named citrin, is bipa rtite in structure, containing a mitochondrial carrier motif and four EF-ha nd domains, suggesting it is a calcium-dependent mitochondrial solute trans porter with a role in urea cycle function.