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Identification of novel mutations in theSLC25A15gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study

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Tessa, Alessandra Fiermonte , Giuseppe Dionisi-Vici , Carlo Paradies , Eleonora Baumgartner m, Matthias R. Nassogne, Marie-Cécile [UCL] Santorelli, Filippo M.

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Human Mutation" - Vol. 30, no. 5, p. 741-748 (2009)
Peer reviewed yes
Publisher JohnWiley & Sons, Inc. ((United States) Hoboken)
issn 1059-7794
e-issn 1098-1004
Publication status Publié
Affiliations UCL - MD/NOPS - Département de neurologie et de psychiatrie
UCL - MD/GYPE - Département de gynécologie, d'obstétrique et de pédiatrie
UCL - (SLuc) Service de neurologie pédiatrique
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Bibliographic reference Tessa, Alessandra ; Fiermonte , Giuseppe ; Dionisi-Vici , Carlo ; Paradies , Eleonora ; Baumgartner m, Matthias R. ; et. al. Identification of novel mutations in theSLC25A15gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study. In: Human Mutation, Vol. 30, no. 5, p. 741-748 (2009)
Permanent URL http://hdl.handle.net/2078.1/120159