Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study†
Alessandra Tessa
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorGiuseppe Fiermonte
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorCarlo Dionisi-Vici
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorEleonora Paradies
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Search for more papers by this authorMatthias R. Baumgartner
Division of Metabolism, Zurich University, Zurich, Switzerland
Search for more papers by this authorYin-Hsiu Chien
Medical Genetics, Taiwan University, Taipei, Taiwan
Search for more papers by this authorCarmela Loguercio
Internal Medicine and Hepatogastroenterology and Neurology, Second University of Naples, Naples, Italy
Search for more papers by this authorHelene Ogier de Baulny
Division of Metabolism, R. Debre Hospital, Paris, France
Search for more papers by this authorMarie-Cecile Nassogne
Pediatric Neurology, St-Luc Hospital, Bruxelles, Belgium
Search for more papers by this authorManuel Schiff
Division of Metabolism, R. Debre Hospital, Paris, France
Search for more papers by this authorFederica Deodato
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Search for more papers by this authorGiancarlo Parenti
Pediatrics, Federico II University, Naples, Italy
Search for more papers by this authorS. Lane Rutledge
Department of Genetics, Alabama University, Birmingham, Alabama
Search for more papers by this authorM. Antonia Vilaseca
Biochemical Unit, Sant Joan de Deu Hospital, Barcelona, Spain
Search for more papers by this authorMariarosa A.B. Melone
Internal Medicine and Hepatogastroenterology and Neurology, Second University of Naples, Naples, Italy
Search for more papers by this authorGioacchino Scarano
Medical Genetics, Azienda Ospedaliera Rummo, Benevento, Italy
Search for more papers by this authorLuiz Aldamiz-Echevarría
Laboratorio de Metabolismo, Hospital de Cruces, Bilbao, Spain
Search for more papers by this authorGuy Besley
Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
Search for more papers by this authorJohn Walter
Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
Search for more papers by this authorEugenia Martinez-Hernandez
Servei de Neurologia, Hospital de Sant Pau, Barcelona, Spain
Search for more papers by this authorJose M. Hernandez
Institut de Bioquímica Clínica, Corporació Sanitària, Barcelona, Spain
Search for more papers by this authorCiro L. Pierri
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Search for more papers by this authorCorresponding Author
Ferdinando Palmieri
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Ferdinando Palmieri, Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, via Orabona, 4-70125 Bari, Italy
Filippo M. Santorelli, Molecular Medicine, IRCCS Children's Hospital Bambino Gesù, Piazza S. Onofrio, 4–00165 Rome, Italy
Search for more papers by this authorCorresponding Author
Filippo M. Santorelli
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Ferdinando Palmieri, Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, via Orabona, 4-70125 Bari, Italy
Filippo M. Santorelli, Molecular Medicine, IRCCS Children's Hospital Bambino Gesù, Piazza S. Onofrio, 4–00165 Rome, Italy
Search for more papers by this authorAlessandra Tessa
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorGiuseppe Fiermonte
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorCarlo Dionisi-Vici
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Alessandra Tessa, Giuseppe Fiermonte, and Carlo Dionisi-Vici contributed equally to this work.
Search for more papers by this authorEleonora Paradies
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Search for more papers by this authorMatthias R. Baumgartner
Division of Metabolism, Zurich University, Zurich, Switzerland
Search for more papers by this authorYin-Hsiu Chien
Medical Genetics, Taiwan University, Taipei, Taiwan
Search for more papers by this authorCarmela Loguercio
Internal Medicine and Hepatogastroenterology and Neurology, Second University of Naples, Naples, Italy
Search for more papers by this authorHelene Ogier de Baulny
Division of Metabolism, R. Debre Hospital, Paris, France
Search for more papers by this authorMarie-Cecile Nassogne
Pediatric Neurology, St-Luc Hospital, Bruxelles, Belgium
Search for more papers by this authorManuel Schiff
Division of Metabolism, R. Debre Hospital, Paris, France
Search for more papers by this authorFederica Deodato
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Search for more papers by this authorGiancarlo Parenti
Pediatrics, Federico II University, Naples, Italy
Search for more papers by this authorS. Lane Rutledge
Department of Genetics, Alabama University, Birmingham, Alabama
Search for more papers by this authorM. Antonia Vilaseca
Biochemical Unit, Sant Joan de Deu Hospital, Barcelona, Spain
Search for more papers by this authorMariarosa A.B. Melone
Internal Medicine and Hepatogastroenterology and Neurology, Second University of Naples, Naples, Italy
Search for more papers by this authorGioacchino Scarano
Medical Genetics, Azienda Ospedaliera Rummo, Benevento, Italy
Search for more papers by this authorLuiz Aldamiz-Echevarría
Laboratorio de Metabolismo, Hospital de Cruces, Bilbao, Spain
Search for more papers by this authorGuy Besley
Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
Search for more papers by this authorJohn Walter
Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
Search for more papers by this authorEugenia Martinez-Hernandez
Servei de Neurologia, Hospital de Sant Pau, Barcelona, Spain
Search for more papers by this authorJose M. Hernandez
Institut de Bioquímica Clínica, Corporació Sanitària, Barcelona, Spain
Search for more papers by this authorCiro L. Pierri
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Search for more papers by this authorCorresponding Author
Ferdinando Palmieri
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy
Ferdinando Palmieri, Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, via Orabona, 4-70125 Bari, Italy
Filippo M. Santorelli, Molecular Medicine, IRCCS Children's Hospital Bambino Gesù, Piazza S. Onofrio, 4–00165 Rome, Italy
Search for more papers by this authorCorresponding Author
Filippo M. Santorelli
Molecular Medicine and Metabolism, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Children's Hospital Bambino Gesù, Rome, Italy
Ferdinando Palmieri, Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, via Orabona, 4-70125 Bari, Italy
Filippo M. Santorelli, Molecular Medicine, IRCCS Children's Hospital Bambino Gesù, Piazza S. Onofrio, 4–00165 Rome, Italy
Search for more papers by this authorCommunicated by Ronald J. A. Wanders
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. Hum Mutat 0, 1–8, 2009. © 2009 Wiley-Liss, Inc.
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