Abstract
L-2-hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a neurometabolic disorder caused by the toxic accumulation of high concentration of L-2-hydroxyglutaric acid in plasma and cerebrospinal fluid. Distinct mutations on the L2HGDH gene have been associated with the clinical and biochemical phenotype. Here we present three novel mutations (Gln197X, Gly211Val and c.540+1 G>A), which increase the present deleterious collection of L2HGDH gene up to 35 mutations that we have compiled in this study. In addition, we used the haplotypic information based on polymorphic markers to demonstrate the common origin of Gly57Arg harboring chromosomes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Duran, M., Kamerling, J., Bakker, H., van Gennip, A. & Wadman, S. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J. Inherit. Metab. Dis. 3, 109–112 (1980).
Rzem, R., Veiga-da-Cunha, M., Noel, G., Goffette, S., Nassogne, M C., Tabarki, B. et al. A gene encoding a putative FAD-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc. Natl. Acad. Sci. USA 101, 16849–16854 (2004).
Topçu, M., Jobard, F., Halliez, S., Coskun, T., Yalcinkayal, C., Gerceker, F. O. et al. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum. Mol. Genet. 13, 2803–2811 (2004).
Rzem, R., Van Schaftingen, E. & Veiga-da-Cunha, M. The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88, 113–116 (2006).
Rzem, R., Vincent, M. F., Van Schaftingen, E. & Veiga-da-Cunha, M. L-2-Hydroxyglutaric aciduria, a defect of metabolite repair. J. Inherit. Metab. Dis. 30, 681–689 (2007).
Vilarinho, L., Cardoso, M. L., Gaspar, P., Barbot, C., Azevedo, L., Diogo, L. et al. Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. Hum. Mut. 26, 395–396 (2005).
Sass, J. O., Jobard, F., Topçu, M., Mahfoud, A., Werlé, E., Cure, S. et al. L-2-Hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J. Inherit. Metab. Dis. 105 (2008).
Larnaout, A., Amouri, R., Kefi, M. & Hentati, F. L-2-Hydroxyglutaric aciduria: clinical and molecular study in three Tunisian families. Identification of a new mutation and inter-familial phenotype variability. J. Inherit. Metab. Dis. 4 (2008).
O’Connor, G., King, M., Salomons, G., Jakobs, C., King, M. & Salomons, G. A novel mutation as a cause of L-2-hydroxyglutaric aciduria. J. Neurol. 256, 672–673 (2009).
Haliloglu, G., Jobard, F., Oguz, K K., Anlar, B., Akalan, N., Coskun, T. et al. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics 39, 119–122 (2008).
Shapiro, M. B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucl. Acids Res. 15, 7155–7174 (1987).
Stenson, P. D., Ball, E. V., Mort, M., Phillips, A. D., Shiel, J. A. & Thomas, N. S. T. The human gene mutation database (HGMD): 2003 update. Hum. Mutat. 21, 577–581 (2003).
Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucl. Acids Res. 28, 27–30 (2000).
Kanehisa, M., Araki, M., Goto, S., Hattori, M., Hirakawa, M., Itoh, M. et al. KEGG for linking genomes to life and the environment. Nucl. Acids Res. 36, D480–D484 (2008).
Kanehisa, M., Goto, S., Hattori, M., Aoki-Kinoshita, K. F., Itoh, M., Kawashima, S. et al. From genomics to chemical genomics: new developments in KEGG. Nucl. Acids Res. 34, D354–D357 (2006).
Drummond, A. J., Cheung, M., Heled, J., Kearse, M., Moir, R., Stones-Havas, S. et al. at http://www.geneious.com/ (2008).
Acknowledgements
LA (C2007-IPATIMUP/AA1) is supported by Fundação para a Ciência e a Tecnologia (FCT) Ciência 2007 and by European Social Fund. IPATIMUP is partially supported by ‘Programa Operacional Ciência e Inovação 2010’ (POCI 2010), VI Programa Quadro (2002–2006).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vilarinho, L., Tafulo, S., Sibilio, M. et al. Identification of novel L2HGDH gene mutations and update of the pathological spectrum. J Hum Genet 55, 55–58 (2010). https://doi.org/10.1038/jhg.2009.110
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2009.110
Keywords
This article is cited by
-
A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
Metabolic Brain Disease (2022)
-
Computational analysis of receptor tyrosine kinase inhibitors and cancer metabolism: implications for treatment and discovery of potential therapeutic signatures
BMC Cancer (2019)
-
Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report
BMC Medical Genetics (2018)
-
A novel compound heterozygous mutation of the L2HGDH gene in a Chinese boy with L-2-hydroxyglutaric aciduria: case report and literature review
Neurological Sciences (2018)