oben

mitoGENE

Vorhalten innovativer und neuester Technologie zur molekularen Diagnostik mitochondrialer Erkrankungen.

Projektstandort: Technische Universität München

Stand der Forschung

Die klinische und genetische Heterogenität mitochondrialer Erkrankungen erschweren die Diagnosestellung. Bei einem Großteil der Patienten bleibt der ursächliche molekulare Defekt unbekannt. Um diese Problem zu adressieren, werden dringend neue Strategien benötigt. Neue Hochdurchsatz-Screening-Methoden ermöglichen die kostengünstige Untersuchung einer Vielzahl von Genen in größeren Patientenkohorten. Auch wenn die Hochdurchsatz-Sequenzierung durchgeführt werden kann, bleibt die vorherige Anreicherung der genomischen Zielregion eine Herausforderung. Bislang wurden dafür zwei Ansätze vorgeschlagen: Die Anreicherung mittels Hybridisierung mit einem spezifischen DNA-Chip oder die Exon/Gen-fokussierte Amplifikation mittels PCR. Beide Vorgehensweisen sind gen-spezifisch und müssen daher krankheitsbezogen entwickelt werden.

Ziele

Ziel dieses Teilprojektes ist es, in drei Schritten, eine umfassende molekulare Diagnostik für mitochondriale Erkrankungen anzubieten unter Einbeziehung neuester technologischer Entwicklungen: (i) das Angebot der Gene für molekulare Diagnostik soll verbessert werden, (ii) 100 Kandidatengenen sollen mit einem Hochdurchsatz Verfahren untersucht werden, (iii) Mitochondriopathie spezifischer Protokolle für neuste DNA-Sequenzierungsverfahren sollen entwickelt werden. Im Rahmen des Antrages soll die molekulare Diagnostik für Mitochondriopathie Patienten effizienter, umfangreicher und günstiger werden.

Projektmanagement und Kontaktadresse

Holger Prokisch, Dr.

Technische Universität München

Institut für Humangenetik

Trogerstr. 22, 81675 München

Tel: +49 89 - 3187 - 2890

Fax: +49 89 - 3187 - 3297

Web: ihg2.helmholtz-muenchen.de

Literatur

Kremer LS, Prokisch H, Identification of Disease-Causing Mutations by Functional Complementation of Patient-Derived Fibroblast Cell Lines.
Methods Mol. Biol. 2017; 1567 - Journal Article

Kopajtich R, Mayr JA, Prokisch H, Analysis of Mitochondrial RNA-Processing Defects in Patient-Derived Tissues by qRT-PCR and RNAseq.
Methods Mol. Biol. 2017; 1567 - Journal Article

Hempel M, Kremer LS, Tsiakas K, Alhaddad B, Haack TB, Löbel U, Feichtinger RG, Sperl W, Prokisch H, Mayr JA, Santer R, LYRM7 - associated complex III deficiency: A clinical, molecular genetic, MR tomographic, and biochemical study.
Mitochondrion. 2017 Jul; - Journal Article

Feichtinger RG, Brunner-Krainz M, Alhaddad B, Wortmann SB, Kovacs-Nagy R, Stojakovic T, Erwa W, Resch B, Windischhofer W, Verheyen S, Uhrig S, Windpassinger C, Locker F, Makowski C, Strom TM, Meitinger T, Prokisch H, Sperl W, Haack TB, Mayr JA, Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.
Oxid Med Cell Longev. 2017; 2017 - Journal Article

Danhauser K, Haack TB, Alhaddad B, Melcher M, Seibt A, Strom TM, Meitinger T, Klee D, Mayatepek E, Prokisch H, Distelmaier F, EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.
Metab Brain Dis. 2016 Jan; - Journal Article

Kremer LS, Distelmaier F, Alhaddad B, Hempel M, Iuso A, Küpper C, Mühlhausen C, Kovacs-Nagy R, Satanovskij R, Graf E, Berutti R, Eckstein G, Durbin R, Sauer S, Hoffmann GF, Strom TM, Santer R, Meitinger T, Klopstock T, Prokisch H, Haack TB, Biallelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy.
Am. J. Hum. Genet. 2016 Jan; - Journal Article

Alston CL, Howard C, Oláhová M, Hardy SA, He L, Murray PG, O'Sullivan S, Doherty G, Shield JP, Hargreaves IP, Monavari AA, Knerr I, McCarthy P, Morris AA, Thorburn DR, Prokisch H, Clayton PE, McFarland R, Hughes J, Crushell E, Taylor RW, A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.
J. Med. Genet. 2016 Apr; - Journal Article

Kremer LS, Stead CL, Lesimple P, Gilleron M, Filaut S, Jardel C, Haack TB, Strom TM, Meitinger T, Azzouz H, Tebib N, Baulny HO, Touati G, Prokisch H, Lombès A, Severe respiratory complex III defect prevents liver adaptation to prolonged fasting.
J. Hepatol. 2016 May; - Journal Article

Olsen RK, Koňaříková E, Giancaspero TA, Mosegaard S, Boczonadi V, Mataković L, Veauville-Merllié A, Terrile C, Schwarzmayr T, Haack TB, Auranen M, Leone P, Galluccio M, Imbard A, Gutierrez-Rios P, Palmfeldt J, Graf E, Vianey-Saban C, Oppenheim M, Schiff Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.
Am. J. Hum. Genet. 2016 Jun; 98(6):1130-45 - Journal Article

Baertling F, Klee D, Haack TB, Prokisch H, Meitinger T, Mayatepek E, Schaper J, Distelmaier F, The many faces of paediatric mitochondrial disease on neuroimaging.
Childs Nerv Syst. 2016 Jul; - Journal Article/Review

Baertling F, Alhaddad B, Seibt A, Budaeus S, Meitinger T, Strom TM, Mayatepek E, Schaper J, Prokisch H, Haack TB, Distelmaier F, Neonatal encephalocardiomyopathy caused by mutations in VARS2.
Metab Brain Dis. 2016 Aug; - Journal Article

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lönnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.
Am. J. Hum. Genet. 2016 Aug; - Journal Article

Klopstock T, Klopstock B, Prokisch H, Mitochondrial replacement approaches: challenges for clinical implementation.
Genome Med. 2016 Nov; 8(1):126 - Journal Article

Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õun CLPB Mutations Cause 3-Methylglutaconic Aciduria, Progressive Brain Atrophy, Intellectual Disability, Congenital Neutropenia, Cataracts, Movement Disorder.
Am. J. Hum. Genet. 2015 Jan; - Journal Article

Kargul J, Irminger-Finger I, Laurent GJ, Mitochondrial diseases: from the lab bench to therapies.
Int. J. Biochem. Cell Biol. 2015 Mar;

Koch J, Freisinger P, Feichtinger RG, Zimmermann FA, Rauscher C, Wagentristl HP, Konstantopoulou V, Seidl R, Haack TB, Prokisch H, Ahting U, Sperl W, Mayr JA, Maier EM, Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype.
Orphanet J Rare Dis. 2015 Apr; 10(1):40 - Journal Article

Huemer M, Karall D, Schossig A, Abdenur JE, Al Jasmi F, Biagosch C, Distelmaier F, Freisinger P, Graham BH, Haack TB, Hauser N, Hertecant J, Ebrahimi-Fakhari D, Konstantopoulou V, Leydiker K, Lourenco CM, Scholl-Bürgi S, Wilichowski E, Wolf NI, Wortmann Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations.
J. Inherit. Metab. Dis. 2015 Apr; - Journal Article

Danhauser K, Herebian D, Haack TB, Rodenburg RJ, Strom TM, Meitinger T, Klee D, Mayatepek E, Prokisch H, Distelmaier F, Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9.
Eur. J. Hum. Genet. 2015 Jun; - Journal Article

Venco P, Bonora M, Giorgi C, Papaleo E, Iuso A, Prokisch H, Pinton P, Tiranti V, Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺.
Front Genet. 2015; 6 - Journal Article

Collet M, Assouline Z, Bonnet D, Rio M, Iserin F, Sidi D, Goldenberg A, Lardennois C, Metodiev MD, Haberberger B, Haack T, Munnich A, Prokisch H, Rötig A, High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood.
Eur. J. Hum. Genet. 2015 Dec; - Journal Article

Diodato D, Invernizzi F, Lamantea E, Fagiolari G, Parini R, Menni F, Parenti G, Bollani L, Pasquini E, Donati MA, Cassandrini D, Santorelli FM, Haack TB, Prokisch H, Ghezzi D, Lamperti C, Zeviani M, Common and Novel TMEM70 Mutations in a Cohort of Italian Patients with Mitochondrial Encephalocardiomyopathy.
JIMD Rep. 2014 Apr; - Journal Article

Melchionda L, Haack TB, Hardy S, Abbink TE, Fernandez-Vizarra E, Lamantea E, Marchet S, Morandi L, Moggio M, Carrozzo R, Torraco A, Diodato D, Strom TM, Meitinger T, Tekturk P, Yapici Z, Al-Murshedi F, Stevens R, Rodenburg RJ, Lamperti C, Ardissone A, Mo Mutations in APOPT1, Encoding a Mitochondrial Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency.
Am. J. Hum. Genet. 2014 Sep; 95(3):315-25 - Journal Article

Müller-Höcker J, Schäfer S, Krebs S, Blum H, Zsurka G, Kunz WS, Prokisch H, Seibel P, Jung A, Oxyphil Cell Metaplasia in the Parathyroids Is Characterized by Somatic Mitochondrial DNA Mutations in NADH Dehydrogenase Genes and Cytochrome c Oxidase Activity-Impairing Genes.
Am. J. Pathol. 2014; 184(11):2922-35 - Journal Article

Kopajtich R, Nicholls TJ, Rorbach J, Metodiev MD, Freisinger P, Mandel H, Vanlander A, Ghezzi D, Carrozzo R, Taylor RW, Marquard K, Murayama K, Wieland T, Schwarzmayr T, Mayr JA, Pearce SF, Powell CA, Saada A, Ohtake A, Invernizzi F, Lamantea E, Sommervi Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy.
Am. J. Hum. Genet. 2014 Dec; 95(6):708-20 - Journal Article

Sperl W, Fleuren L, Freisinger P, Haack TB, Ribes A, Feichtinger RG, Rodenburg RJ, Zimmermann FA, Koch J, Rivera I, Prokisch H, Smeitink JA, Mayr JA, The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders.
J. Inherit. Metab. Dis. 2014 Dec; - Journal Article

Tischner C, Hofer A, Wulff V, Stepek J, Dumitru I, Becker L, Haack T, Kremer L, Datta AN, Sperl W, Floss T, Wurst W, Chrzanowska-Lightowlers Z, de Angelis MH, Klopstock T, Prokisch H, Wenz T, MTO1 mediates tissue-specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.
Hum. Mol. Genet. 2014 Dec; - Journal Article

Falk MJ, Shen L, Gonzalez M, Leipzig J, Lott MT, Stassen AP, Diroma MA, Navarro-Gomez D, Yeske P, Bai R, Boles RG, Brilhante V, Ralph D, DaRe JT, Shelton R, Terry SF, Zhang Z, Copeland WC, van Oven M, Prokisch H, Wallace DC, Attimonelli M, Krotoski D, Zu Mitochondrial Disease Sequence Data Resource (MSeqDR): A global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.
Mol. Genet. Metab. 2014 Dec; - Review

Haack TB, Rolinski B, Haberberger B, Zimmermann F, Schum J, Strecker V, Graf E, Athing U, Hoppen T, Wittig I, Sperl W, Freisinger P, Mayr JA, Strom TM, Meitinger T, Prokisch H, Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings.
J. Inherit. Metab. Dis. 2013 Jan; 36(1):55-62 - Journal Article

Schulte EC, Claussen MC, Jochim A, Haack T, Hartig M, Hempel M, Prokisch H, Haun-Jünger U, Winkelmann J, Hemmer B, Förschler A, Ilg R, Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.
Mov. Disord. 2013 Feb; 28(2):224-7 - Journal Article

Haack TB, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ, Baruffini E, Walther A, Danhauser K, Zimmermann FA, Husain RA, Schum J, Mundy H, Ferrero I, Strom TM, Meitinger T, Taylor RW, Minczuk M, Mayr JA, Prokisch H, ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy.
Am. J. Hum. Genet. 2013 Jul; - Journal Article

Bonnen PE, Yarham JW, Besse A, Wu P, Faqeih EA, Al-Asmari AM, Saleh MA, Eyaid W, Hadeel A, He L, Smith F, Yau S, Simcox EM, Miwa S, Donti T, Abu-Amero KK, Wong LJ, Craigen WJ, Graham BH, Scott KL, McFarland R, Taylor RW, Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance.
Am. J. Hum. Genet. 2013 Aug; - Journal Article

Hartig M, Prokisch H, Meitinger T, Klopstock T, Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN).
Int. Rev. Neurobiol. 2013; 110 - Journal Article

Jackson CB, Nuoffer JM, Hahn D, Prokisch H, Haberberger B, Gautschi M, Häberli A, Gallati S, Schaller A, Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.
J. Med. Genet. 2013 Dec; - Journal Article

Haack TB, Gorza M, Danhauser K, Mayr JA, Haberberger B, Wieland T, Kremer L, Strecker V, Graf E, Memari Y, Ahting U, Kopajtich R, Wortmann SB, Rodenburg RJ, Kotzaeridou U, Hoffmann GF, Sperl W, Wittig I, Wilichowski E, Schottmann G, Schuelke M, Plecko B, Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.
Mol. Genet. Metab. 2013 Dec; - Journal Article

van den Bosch BJ, Gerards M, Sluiter W, Stegmann AP, Jongen EL, Hellebrekers DM, Oegema R, Lambrichs EH, Prokisch H, Danhauser K, Schoonderwoerd K, de Coo IF, Smeets HJ, Defective NDUFA9 as a novel cause of neonatally fatal complex I disease.
J. Med. Genet. 2012 Jan; 49(1):10-5 - Journal Article

Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, Bley A, Diogo L, Grillo E, Te Water Naudé J, Strom TM, Bertini E, Prokisch H, van der Knaap MS, Zeviani M, Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations.
Brain. 2012 May; 135(Pt 5):1387-94 - Journal Article

Ghezzi D, Baruffini E, Haack TB, Invernizzi F, Melchionda L, Dallabona C, Strom TM, Parini R, Burlina AB, Meitinger T, Prokisch H, Ferrero I, Zeviani M, Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis.
Am. J. Hum. Genet. 2012 Jun; 90(6):1079-87 - Journal Article

Haack TB, Hogarth P, Kruer MC, Gregory A, Wieland T, Schwarzmayr T, Graf E, Sanford L, Meyer E, Kara E, Cuno SM, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Frucht S, Hanspal E, Schrander-Stumpel C, Héron D, Mignot C, Ga Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.
Am. J. Hum. Genet. 2012 Dec; 91(6):1144-9 - Journal Article

Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E, Zschocke J, Strom TM, Traub T, Okun JG, Meitinger T, Hoffmann GF, Prokisch H, Kölker S, DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria.
Am. J. Hum. Genet. 2012 Dec; 91(6):1082-7 - Journal Article

Haack TB, Makowski C, Yao Y, Graf E, Hempel M, Wieland T, Tauer U, Ahting U, Mayr JA, Freisinger P, Yoshimatsu H, Inui K, Strom TM, Meitinger T, Yonezawa A, Prokisch H, Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.
J. Inherit. Metab. Dis. 2012 Nov; 35(6):943-8 - Journal Article

Deschauer M, Gaul C, Behrmann C, Prokisch H, Zierz S, Haack TB, C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.
J. Neurol. 2012 Nov; 259(11):2434-9 - Journal Article

Gerards M, van den Bosch BJ, Danhauser K, Serre V, van Weeghel M, Wanders RJ, Nicolaes GA, Sluiter W, Schoonderwoerd K, Scholte HR, Prokisch H, Rötig A, de Coo IF, Smeets HJ, Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene.
Brain. 2011 Jan; 134(Pt 1):210-9 - Journal Article

Mayr JA, Freisinger P, Schlachter K, Rolinski B, Zimmermann FA, Scheffner T, Haack TB, Koch J, Ahting U, Prokisch H, Sperl W, Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.
Am. J. Hum. Genet. 2011 Dec; 89(6):806-12 - Journal Article

Elstner M, Muller SK, Leidolt L, Laub C, Krieg L, Schlaudraff F, Liss B, Morris C, Turnbull DM, Masliah E, Prokisch H, Klopstock T, Bender A, Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.
2011 Dec; 4(1):43 - Journal Article

Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.
Am. J. Hum. Genet. 2011 Oct; 89(4):543-50 - Journal Article

Pham TT, Giesert F, Röthig A, Floss T, Kallnik M, Weindl K, Hölter SM, Ahting U, Prokisch H, Becker L, Klopstock T, Hrabé de Angelis M, Beyer K, Görner K, Kahle PJ, Vogt Weisenhorn DM, Wurst W, DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments.
Genes Brain Behav. 2010 Apr; 9(3):305-17 - Journal Article

O'Toole JF, Liu Y, Davis EE, Westlake CJ, Attanasio M, Otto EA, Seelow D, Nurnberg G, Becker C, Nuutinen M, Kärppä M, Ignatius J, Uusimaa J, Pakanen S, Jaakkola E, van den Heuvel LP, Fehrenbach H, Wiggins R, Goyal M, Zhou W, Wolf MT, Wise E, Helou J, All Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
J. Clin. Invest. 2010 Mar; 120(3):791-802 - Journal Article

Herzer M, Koch J, Prokisch H, Rodenburg R, Rauscher C, Radauer W, Forstner R, Pilz P, Rolinski B, Freisinger P, Mayr JA, Sperl W, Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect.
Neuropediatrics. 2010 Feb; 41(1):30-4 - Journal Article

Ahting U, Floss T, Uez N, Schneider-Lohmar I, Becker L, Kling E, Iuso A, Bender A, de Angelis MH, Gailus-Durner V, Fuchs H, Meitinger T, Wurst W, Prokisch H, Klopstock T, Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import.
Biochim. Biophys. Acta. 2009 May; 1787(5):371-6 - Journal Article

Elstner M, Andreoli C, Klopstock T, Meitinger T, Prokisch H, The mitochondrial proteome database: MitoP2.
Meth. Enzymol. 2009; 457 - Journal Article

Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, D'Adamo P, Gasparini P, Strom TM, Prokisch H, Invernizzi F, Ferrero I, Zeviani M, SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy.
Nat. Genet. 2009 Jun; 41(6):654-6 - Journal Article