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MPV17-Associated Hepatocerebral Mitochondrial DNA Depletion Syndrome: New Patients and Novel Mutations

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MPV17-Associated Hepatocerebral Mitochondrial DNA Depletion Syndrome: New Patients and Novel Mutations Molecular Genetics and Metabolism 99 (2010) 300–308 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: New patients and novel mutations Ayman W. El-Hattab a, Fang-Yuan Li a, Eric Schmitt a, Shulin Zhang a, William J. Craigen a,b, Lee-Jun C. Wong a,* a Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor plaza, Houston, TX 77030, USA b Department of Pediatrics, Baylor College of Medicine, 1 Baylor plaza, Houston, TX 77030, USA article info abstract Article history: Mitochondrial DNA depletion syndromes are autosomal recessive diseases characterized by a severe Received 4 August 2009 decrease in mitochondrial DNA content leading to dysfunction of the affected organ. They are phenotyp- Received in revised form 7 October 2009 ically heterogeneous and classified as myopathic, encephalomyopathic, or hepatocerebral. The latter Accepted 7 October 2009 group has been associated with mutations in TWINKLE, POLG1, DGUOK genes and recently with mutations Available online 13 October 2009 in the MPV17 gene. MPV17 encodes a mitochondrial inner membrane protein and plays an as yet poorly understood role in mitochondrial DNA maintenance. Mutations in the MPV17 gene have been reported in Keywords: patients who came to medical attention during infancy with liver failure, hypoglycemia, failure-to-thrive MPV17 gene mutations and neurological symptoms. In addition, a homozygous p.R50Q mutation has been identified in patients Mitochondrial DNA depletion Hepatocerebral mitochondrial disease with Navajo neurohepatopathy. To date, 13 different mutations in 21 patients have been reported. We report eight new patients with seven novel mutations, including four missense mutations (c.262A>G (p.K88E), c.280G>C (p.G94R), c.293C>T (p.P98L), and c.485C>A (p.A162D)), one in-frame deletion (c.271_273del3 (p.L91del)), one splice site substitution (c.186+2T>C), and one insertion (c.22_23insC). The p.R50Q mutation, which occurs in a CpG dinucleotide, is the most common MPV17 mutation and, to date, has only been found in the homozygous state. Clinically, patients homozygous for p.R50Q or com- pound heterozygous for the p.G94R and p.P98L mutations have a better prognosis, with all the other mutations associated with early death if not treated by liver transplantation. Localizing the mutations within the predicted MPV17 protein structure reveals clustering of mutations in the region of the puta- tive protein kinase C phosphorylation site. Ó 2010 Elsevier Inc. All rights reserved. Introduction organ or a combination of organs, including muscle, liver, brain, and kidney. Clinically, MDS are usually classified as one of three Mitochondrial diseases are a clinically heterogeneous group of forms: a myopathic form (OMIM #609560) associated with muta- disorders that result from mitochondrial respiratory chain dys- tions in the thymidine kinase 2 (TK2) gene [5] or the p53-induced function that can be caused by defects in mitochondrial DNA ribonucleotide reductase B subunit (RRM2B) gene [6,7], an enceph- (mtDNA) or nuclear genes involved in mtDNA biogenesis and alomyopathic form (OMIM #612073) associated with mutations in maintenance [1]. Mendelian disorders due to defects in nuclear the ATP-dependant succinyl CoA synthase gene (SUCLA2) [8] or the genes can be associated with large-scale rearrangements of mtDNA GTP-dependant succinyl CoA synthase gene (SUCLG1) [9], and a (mtDNA deletion syndromes) or with reduction in the mtDNA copy hepatocerebral form (OMIM #251880) associated with mutations number (mtDNA depletion syndromes, MDS) [2]. in either the Twinkle (PEO1) gene [10], the polymerase-cA(POLG1) MDS are autosomal recessive disorders that primarily affect in- gene [11], the deoxyguanosine kinase (DGUOK) gene [12], or, more fants or children and are characterized by a severe decrease of recently, with mutations in the MPV17 gene [3]. mtDNA content leading to organ dysfunction that is likely due to Mutations in the MPV17 gene were initially identified in insufficient synthesis of respiratory chain components [3,4]. MDS patients who presented in the first year of life with liver failure, are phenotypically heterogeneous and may affect either a specific hypoglycemia, failure-to-thrive and neurological symptoms [3,13]. Subsequently, Karadimas and colleagues [14] reported a homozygous p.R50Q mutation in six patients with Navajo neuro- * Corresponding author. Address: Department of Molecular and Human Genetics, hepatopathy (NNH), an autosomal recessive multisystem disorder Baylor College of Medicine, 1 Baylor Plaza, NAB 2015, Houston, TX 77030, USA. Fax: +1 713 798 8937. prevalent in the Native American Navajo population that manifests E-mail address: [email protected] (L.-J.C. Wong). as liver disease, sensory and motor neuropathy, corneal anesthesia 1096-7192/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2009.10.003 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 99 (2010) 300–308 301 and scarring, cerebral leukoencephalopathy, failure-to-thrive, and activities are expressed with respect to both the total protein and metabolic acidosis [15,16]. Recently, additional mutations in the CS activity. MPV17 gene have also been reported [4,17–19]. To date, 13 differ- ent mutations in 21 patients have been observed. In this report we Results describe eight new patients with seven novel mutations. We also summarize and compare the clinical manifestations and the bio- Patients chemical and molecular results for these and the 21 previously re- ported patients. Eight patients with MPV17-associated hepatocerebral MDS whose blood and tissue samples were sent to Mitochondrial Diag- nostic Laboratory at Baylor College of Medicine were analyzed bio- Materials and methods chemically and molecularly. All the patients developed liver failure in infancy, except patient 8, who is of Navajo heritage and pre- Molecular studies sented with liver dysfunction. Patient 7 had liver cirrhosis and developed hepatocellular carcinoma. Common neurological find- The DNA was extracted from peripheral blood, cultured skin ings were developmental delay, hypotonia, muscle weakness, and fibroblasts, muscle, or liver tissue using Gentra DNA isolation kits peripheral neuropathy. Failure-to-thrive, hypoglycemia, and lactic according to manufacturer’s instructions (Gentra Systems Inc., acidosis were also common findings. Electron transport chain Minneapolis, MN). The mtDNA copy number in various tissues (ETC.) activities in muscle tissue were measured in two patients. was determined by the real-time quantitative polymerase chain Patient 2 has low complex I and complexes II + III activities and pa- reaction (RT-qPCR) using primers specific for the mitochondrial tient 3 has low complex I and complex IV activities. MtDNA deple- transfer RNALeu (uur) gene and nuclear single-copy gene, b-2- tion was confirmed by mtDNA copy number assessments, which microglobulin [20]. The RT-qPCR was performed in duplicate for ranged between 25% and 76% in muscle, 28% and 70% in blood, each reaction. MtDNA depletion was diagnosed by comparing pa- and 6% and 21% in liver (Table 1). tient’s mtDNA copy number with tissue and age matched controls. MPV17 gene mutations Sequence-specific oligonucleotide primers linked to M13 univer- sal primers were designed to amplify all coding exons and the flank- In the eight reported patients, ten different mutations were ing intronic 50 nucleotides of the MPV17 gene. PCR products were identified, among which seven are novel (Tables 1 and 2). Patient purified on ExcelaPure 96-well ultrafiltration PCR purification plates 1 is homozygous for a novel c.262A>G (p.K88E) mutation. Lysine (Edge Bio-Systems, Gaithersburg, MD). Sequencing reactions were at position 88 is evolutionarily conserved from zebra fish to human performed with the BigDye Terminator cycle sequencing kit (version and is conserved as the basic amino acid arginine in yeast. It is lo- 3.1), purified with Performa DTR 96-well V3 short plates (Edge Bio- cated near the putative protein kinase C phosphorylation site. The Systems), and analyzed on an ABI3730XL automated DNA sequencer SIFT and PolyPhen algorithms predict p.K88E to be deleterious. Pa- with Sequencing Analysis Software version 5.1 (Applied Biosys- tient 2 is compound heterozygous for two novel missense muta- tems). DNA sequences were aligned with the MPV17 reference se- tions; c.280G>C (p.G94R) and c.293C>T (p.P98L). Glycine at quence (GenBank accession No. NT_022184.14) using Mutation position 94 shows evolutionary conservation from zebra fish to hu- Surveyor version 2.6.1 (SoftGeneticsÒ, State College, PA). Due to man, and PolyPhen predicts p.G94R to be deleterious. Additionally, the lack of a functional assay for the mutant proteins, the pathoge- c.280 is the first nucleotide of exon 5; therefore, this mutation may nicity of novel mutants was determined by clinical phenotype, affect splicing. Proline at position 98 is conserved from yeast to hu- amino acid conservation, and prediction algorithms, including SIFT man, and PolyPhen predicts p.P98L to be deleterious. Patient 3 is and PolyPhen (http://sift.jcvi.org; http://genetics.bwh.harvard. compound heterozygous for an in-frame deletion c.263_265del3 edu/pph/). (p.K88del) that was reported previously [17] and for a non-coding variant at the 50UTR, c.-22_-16del7, the significance of which is un- known. Patient 4 harbors two novel heterozygous mutations;
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