TY - JOUR
T1 - Identification of novel mutations in the SLC25A15 Gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
T2 - A clinical, molecular, and functional study
AU - Tessa, Alessandra
AU - Fiermonte, Giuseppe
AU - Dionisi-Vici, Carlo
AU - Paradies, Eleonora
AU - Baumgartner, Matthias R.
AU - Chien, Yin Hsiu
AU - Loguercio, Carmela
AU - De Baulny, Helene Ogier
AU - Nassogne, Marie Cecile
AU - Schiff, Manuel
AU - Deodato, Federica
AU - Parenti, Giancarlo
AU - Rutledge, S. Lane
AU - Antonia Vilaseca, M.
AU - Melone, Mariarosa A B
AU - Scarano, Gioacchino
AU - Aldamiz-Echevarria, Luiz
AU - Besley, Guy
AU - Walter, John
AU - Martinez-Hernandez, Eugenia
AU - Hernandez, Jose M.
AU - Pierri, Ciro L.
AU - Palmieri, Ferdinando
AU - Santorelli, Filippo M.
PY - 2009/5
Y1 - 2009/5
N2 - Hyperornithinemia-hyperammonemia-homoci-trullinuria (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 microrear-rangement. 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.
AB - Hyperornithinemia-hyperammonemia-homoci-trullinuria (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 microrear-rangement. 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.
KW - HH
KW - Homocitrullinuria
KW - Hyperammonemia
KW - Hyperornithinemia
KW - ORC1
KW - SLC25A15
UR - http://www.scopus.com/inward/record.url?scp=66749177843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66749177843&partnerID=8YFLogxK
U2 - 10.1002/humu.20930
DO - 10.1002/humu.20930
M3 - Article
C2 - 19242930
AN - SCOPUS:66749177843
VL - 30
SP - 741
EP - 748
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 5
ER -