The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome N. Brahimi a,1 , M. Jambou a,1 , E. Sarzi b , V. Serre b , N. Boddaert c,d,e,g , S. Romano a , P. de Lonlay a,b,c,g , A. Slama c,f , A. Munnich a,b,c,g , A. Rötig b,c , J.P. Bonnefont a,b,c,g , A.S. Lebre a,b,c, * a AP-HP, Hôpital Necker-Enfants Malades, Département de Génétique, Batiment Lavoisier 3 è étage, 149 rue de Sèvres, Paris F-75015, France b Inserm, U781, Hôpital Necker-Enfants Malades, Paris F-75015, France c AP-HP, Centre de Référence Maladies Mitochondriales, Paris F-75015, France d AP-HP, Hôpital Necker-Enfants Malades, Service de radiologie pédiatrique, Paris F-75015, France e Inserm, U797, CEA, Neuroimagerie en psychiatrie, Service hospitalier Frédéric Joliot, Orsay F-91400, France f AP-HP, Hôpital Bicêtre, Service de Biochimie, Kremlin-Bicêtre F-94270, France g Université Paris Descartes, Faculté de Médecine René Descartes, Paris F-75015, France article info Article history: Received 18 February 2009 Received in revised form 20 March 2009 Accepted 20 March 2009 Available online 27 March 2009 Keywords: Mitochondrial DNA depletion syndrome DGUOK gene Hepatoencephalopathy Founder mutation In silico structure analysis abstract Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homo- zygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal mye- lination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position À62) and is predicted to result in a larger protein with an in- frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the a5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segre- gated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population. Ó 2009 Elsevier Inc. All rights reserved. Introduction DGUOK (deoxyguanosine kinase, dGK), MPV17, and POLG (poly- merase gamma) mutations are the major causes of mitochondrial DNA (mtDNA) depletion associated with hepatocerebral syndrome [1]. Patients with dGK deficiency typically present with liver dys- function at birth or within a few months, with or without neuro- logical impairment, and most die before 4 years of age due to liver failure [2–6]. Subjects can have elevated serum tyrosine or phenylalanine [6]. Neurological disease may be apparent by the presence of nystagmus, developmental delay, or profound hypoto- nia. MRI in DGUOK patients is usually normal before 1 year [2,6]. However, magnetic resonance spectroscopy (MRS) can reveal a lac- tate peak [2,6]. Genotype–phenotype correlation studies show that patients who harbor null mutations in the DGUOK gene usually have early onset liver failure and significant neurological disease and die before 2 years of age [6]. Patients carrying missense muta- tions usually have isolated liver disease and live to the age of four without liver transplants [6]. The presence of significant neurolog- ical signs should preclude the consideration of liver transplanta- tion [7]. dGK is a member of the deoxyribonucleoside kinase family in- volved in phosphorylation of deoxyribonucleosides. In mammals, there are four deoxyribonucleoside kinases with overlapping spec- ificities: two cytoplasmic enzymes, thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), and two mitochondrial enzymes, thy- midine kinase 2 (TK2) and deoxyguanosine kinase (dGK). The hu- man dGK protein is highly specific for purine substrates [8]. Johansson et al. crystalized dGK as a dimeric protein [8]. Each monomer has an ab architecture (with nine a helices) with a central five-stranded parallel sheet [8]. Here, we describe the clin- ical, radiological, and biological features of three children with 1096-7192/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2009.03.007 * Corresponding author. Address: AP-HP, Hôpital Necker-Enfants Malades, Département de Génétique, Batiment Lavoisier 3 è étage, 149 rue de Sèvres, Paris F-75015, France. Fax: +33 1 71 19 64 20. E-mail address: anne-sophie.lebre@nck.aphp.fr (A.S. Lebre). 1 These authors contributed equally to this work. Molecular Genetics and Metabolism 97 (2009) 221–226 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme