title: Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.
abstract: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle. With the exception of the French-Canadian founder effect, no common mutation has been detected in other populations. In this study, we collected 16 additional HHH cases and expanded the spectrum of SLC25A15/ORC1 mutations. Eleven novel mutations were identified including six new missense and one microrearrangement. We also measured the transport properties of the recombinant purified proteins in reconstituted liposomes for four new and two previously reported missense mutations and proved that the transport activities of these mutant forms of ORC1 were reduced as compared with the wild-type protein; residual activity ranged between 4% and 19%. Furthermore, we designed three-dimensional (3D)-modeling of mutant ORC1 proteins. While modeling the changes in silico allowed us to obtain new information on the pathomechanisms underlying HHH syndrome, we found no clear-cut genotype-phenotype correlations. Although patient metabolic alterations responded well to low-protein therapy, predictions concerning the long-term evolution of HHH syndrome remain uncertain. The preference for a hepatic rather than a neurological presentation at onset also continues, largely, to elude us. Neither modifications in oxidative metabolism-related energy, such as those expected in different mtDNA haplogroups, nor sequence variants in SLC25A2/ORC2 seem to be crucial. Other factors, including protein stability and function, and ORC1-ORC2 structural interactions should be further investigated.
authors.affiliation: Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico Children's Hospital Bambino Gesù, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Eleonora
authors.initials: E
authors.lastname: Paradies
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Carmela
authors.initials: C
authors.lastname: Loguercio
authors.forename: Helene Ogier
authors.initials: HO
authors.lastname: de Baulny
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Nassogne
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.forename: Federica
authors.initials: F
authors.lastname: Deodato
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.forename: S Lane
authors.initials: SL
authors.lastname: Rutledge
authors.forename: M Antonia
authors.initials: MA
authors.lastname: Vilaseca
authors.forename: Mariarosa A B
authors.initials: MA
authors.lastname: Melone
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Luiz
authors.initials: L
authors.lastname: Aldamiz-Echevarría
authors.forename: Guy
authors.initials: G
authors.lastname: Besley
authors.forename: John
authors.initials: J
authors.lastname: Walter
authors.forename: Eugenia
authors.initials: E
authors.lastname: Martinez-Hernandez
authors.forename: Jose M
authors.initials: JM
authors.lastname: Hernandez
authors.forename: Ciro L
authors.initials: CL
authors.lastname: Pierri
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D000328:Adult; D026923:Amino Acid Transport Systems, Basic / Q000737:chemistry / Q000235:genetics*; D001692:Biological Transport; D002648:Child; D002675:Child, Preschool; D002956:Citrulline / Q000031:analogs & derivatives* / Q000652:urine; D004926:Escherichia coli; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000453:epidemiology / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins; D050505:Mutant Proteins / Q000302:isolation & purification; D009154:Mutation / Q000235:genetics*; D009952:Ornithine / Q000097:blood*; D017433:Protein Structure, Secondary; D013577:Syndrome
chemical_list: D026923:Amino Acid Transport Systems, Basic; D033681:Mitochondrial Membrane Transport Proteins; D050505:Mutant Proteins; C442901:SLC25A15 protein, human; C488998:SLC25A2 protein, human; C001352:homocitrulline; D002956:Citrulline; D009952:Ornithine