title: A new Caucasian case of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD): a clinical, molecular, and functional study.
abstract: Citrin is the liver-specific isoform of the mitochondrial aspartate/glutamate carrier (AGC2). AGC2 deficiency is an autosomal recessive disorder with two age related phenotypes: neonatal intrahepatic cholestasis (NICCD, OMIM#605814) and adult-onset type II citrullinemia (CTLN2, OMIM#603471). NICCD arises within the first few weeks of life resulting in prolonged cholestasis and metabolic abnormalities including aminoacidemia and galactosuria. Usually symptoms disappear within the first year of life, thus making a diagnosis difficult after this time. In this study we report a new Caucasian case of NICCD, a seven week old Romanian boy with prolonged jaundice. Sequencing of the AGC2 gene showed a novel homozygous missense double-nucleotide (doublet) mutation, which produces the change of the glycine at position 437 into glutamate. Functional studies, carried out on the recombinant mutant protein, for the first time demonstrated, that NICCD is caused by a reduced transport activity of AGC2. The presence of AGC2 deficiency in other ethnic groups besides Asian population suggests further consideration for NICCD diagnosis of any neonate with an unexplained cholestasis; a prompt diagnosis is crucial to resolve the metabolic decompensation with an appropriate dietary treatment.
authors.affiliation: Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy. gfierm@farmbiol.uniba.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parisi
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Francesco
authors.initials: F
authors.lastname: De Leonardis
authors.forename: Giuliano
authors.initials: G
authors.lastname: Torre
authors.forename: Ciro Leonardo
authors.initials: CL
authors.lastname: Pierri
authors.forename: Alessia
authors.initials: A
authors.lastname: Saccari
authors.forename: Francesco Massimo
authors.initials: FM
authors.lastname: Lasorsa
authors.forename: Angelo
authors.initials: A
authors.lastname: Vozza
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D020159:Citrullinemia / Q000175:diagnosis* / Q000235:genetics; D017124:Conserved Sequence; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D011994:Recombinant Proteins; C119629:SLC25A13 protein, human