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Mitochondrial Dna Sequence Variation in Finnish Patients with Maternally Inherited Type 2 Diabetes, Epilepsy and Mitochondrial Disease: Risk and Novel Mutations

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Mitochondrial Dna Sequence Variation in Finnish Patients with Maternally Inherited Type 2 Diabetes, Epilepsy and Mitochondrial Disease: Risk and Novel Mutations D 1220 OULU 2013 D 1220 UNIVERSITY OF OULU P.O.BR[ 00 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA SERIES EDITORS DMEDICA Heidi Soini ASCIENTIAE RERUM NATURALIUM Heidi Soini Professor Esa Hohtola MITOCHONDRIAL DNA BHUMANIORA SEQUENCE VARIATION University Lecturer Santeri Palviainen CTECHNICA IN FINNISH PATIENTS WITH Postdoctoral research fellow Sanna Taskila MATERNALLY INHERITED TYPE DMEDICA Professor Olli Vuolteenaho 2 DIABETES, EPILEPSY AND ESCIENTIAE RERUM SOCIALIUM MITOCHONDRIAL DISEASE: University Lecturer Hannu Heikkinen RISK AND NOVEL MUTATIONS FSCRIPTA ACADEMICA Director Sinikka Eskelinen GOECONOMICA Professor Jari Juga EDITOR IN CHIEF Professor Olli Vuolteenaho PUBLICATIONS EDITOR Publications Editor Kirsti Nurkkala UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE, ISBN 978-952-62-0293-8 (Paperback) INSTITUTE OF CLINICAL MEDICINE, ISBN 978-952-62-0294-5 (PDF) DEPARTMENT OF NEUROLOGY; ISSN 0355-3221 (Print) OULU UNIVERSITY HOSPITAL, ISSN 1796-2234 (Online) MEDICAL RESEARCH CENTER OULU ACTA UNIVERSITATIS OULUENSIS D Medica 1220 HEIDI SOINI MITOCHONDRIAL DNA SEQUENCE VARIATION IN FINNISH PATIENTS WITH MATERNALLY INHERITED TYPE 2 DIABETES, EPILEPSY AND MITOCHONDRIAL DISEASE: RISK AND NOVEL MUTATIONS Academic Dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium 1 of Oulu University Hospital, on 5 December 2013, at 12 noon UNIVERSITY OF OULU, OULU 2013 Copyright © 2013 Acta Univ. Oul. D 1220, 2013 Supervised by Professor Kari Majamaa Reviewed by Professor Antonio Salas Professor Wolfram Kunz ISBN 978-952-62-0293-8 (Paperback) ISBN 978-952-62-0294-5 (PDF) ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) Cover Design Raimo Ahonen JUVENES PRINT TAMPERE 2013 Soini, Heidi, Mitochondrial DNA sequence variation in Finnish patients with maternally inherited type 2 diabetes, epilepsy and mitochondrial disease: risk and novel mutations. University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute of Clinical Medicine, Department of Neurology; Oulu University Hospital, Medical Research Center Oulu Acta Univ. Oul. D 1220, 2013 Abstract Cellular energy is produced by the mitochondria via oxidative phosphorylation. In addition to nuclear DNA; the mitochondrion contains circular mitochondrial DNA (mtDNA) molecules. MtDNA is maternally inherited and encodes 37 genes that are crucial for the energy production of the cell. Mutations in the mtDNA cause mitochondrial diseases that manifest as maternally inherited energy metabolism disorders. Common symptoms include diabetes mellitus, myopathy, sensorineural hearing impairment, eye and vision problems, epilepsy and brain manifestations (encephalopathy). Mitochondrial mutations are often heteroplasmic; cells and tissues contain a mix of healthy and mutated mtDNA. The percentage of mutated mtDNA contributes to the severity of symptoms. Mitochondrial DNA also contains numerous polymorphisms; some of which have been reported to be non-neutral, thus contributing to the occurrence of common diseases. Whole mtDNA sequences were obtained from patients with diabetes mellitus (64), epilepsy (79) and unknown mitochondrial disease (66) using conformation-sensitive gel electrophoresis and direct sequencing. Whole mtDNA sequences of a Finnish family with ataxia were also obtained. Restriction fragment length analysis and cloning were used for heteroplasmy quantification. Whole mitochondrial genomes were organized into phylogenetic trees. All nonsynonymous mutations were analyzed with pathogenicity predicting algorithms (SNAP, PolyPhen-2, PMut, SIFT Blink). Non-neutral risk mutations were identified in diabetes mellitus and epilepsy patients. These patients had maternal relatives with diabetes, epilepsy and/or sensorineural hearing impairment. M. 3010A>G and m.16189T>C were found in increased frequency in diabetics and the haplogroup U5b variant m.15218A>G was detected more often among patients with epilepsy. These mutations were predicted to be deleterious in effect. Mitochondrial haplogroup V was found in increased frequency in matrilineal diabetes mellitus patients. We identified an m.8993T>C mutation in a Finnish family with ataxia. This mutation caused an adult-onset ataxic phenotype; previous studies have reported only juvenile onset phenotypes. Novel and rare mtDNA mutations were discovered in patients with an unspecified mitochondrial disease phenotype; these included an insertion m.7585insT and a novel MTTT mutation m. 15933G>A. This thesis emphasizes the importance of full mtDNA sequencing in patients with a suspected mitochondrial disease; novel mutations remain undetected if only the most common mutations are screened. In addition, the increasing importance of non-neutral mtDNA risk variants is supported by the findings of this thesis. In the future, individualized genetics and information on personal risk alleles will become even more important for maintaining health on a personal level. Keywords: diabetes mellitus, epilepsy, haplogroup, mitochondria, mitochondrial disease, mitochondrial DNA, mtDNA, nonsynonymous mutation, pathogenicity prediction, phylogeny, risk mutation Soini, Heidi, Mitokondriaalisen DNA:n muutokset maternaalisesti periytyvää diabetesta, epilepsiaa ja mitokondriotautia sairastavilla potilailla. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisen lääketieteen laitos, Neurologia; Oulun yliopistollinen sairaala, Medical Research Center Oulu Acta Univ. Oul. D 1220, 2013 Tiivistelmä Mitokondriot ovat energiaa tuottavia soluelimiä. Mitokondrioissa on oma rengasmainen mito- kondriaalinen DNA (mtDNA), joka esiintyy solussa useana kopiona. MtDNA periytyy vain äidin kautta, joten kaikille lapsille periytyy sama mitokondriaalinen DNA. MtDNA koodaa 37:ää gee- niä, jotka ovat tärkeitä solun energiantuotannolle. Geenimuutos mtDNA:ssa voi aiheuttaa äidiltä periytyvän mitokondriotaudin. Mitokondriotaudit ovat energia-aineenvaihdunnan sairauksia, jois- sa tavallisia oireita ovat diabetes mellitus, lihasoireet (esimerkiksi lihasten ennenaikainen väsy- mys, myopatia), sydänlihasoireet, maksaoireet, silmä- ja näköoireet, aistimistyyppinen kuulovika sekä aivo-oireet, kuten epilepsia. Oireet vaihtelevat huomattavasti, ja sama mutaatio voi aiheuttaa hyvin erilaisia taudinkuvia. Vakavimmillaan mitokondriotauti voi johtaa kuolemaan jo varhaislap- suudessa. Mutaation prosenttiosuus eli heteroplasmia-aste on usein oireiden vakavuutta määrittele- vä tekijä. Mitokondriaalinen DNA muuntuu nopeasti evoluution aikana, joten siinä esiintyy paljon normaalia vaihtelua (polymorfioita). Osa näistä polymorfioista on kuitenkin todettu lievästi haital- lisiksi, ja ne lisäävät riskiä sairastua kansanterveydellisesti yleisiin sairauksiin, kuten diabetekseen. Kartoitimme koko mitokondriogenomin muutokset eri potilasryhmiltä, joihin kuului diabetes- ta, epilepsiaa ja ataksiaa sairastavia potilaita. Lisäksi tutkittiin potilaita, joilla epäiltiin mitokond- riotautia. Keskeiset käytetyt menetelmät olivat DNA:n rakenteellisia muutoksia havaitseva geelie- lektroforeesi ja sekvensointi. Määritimme heteroplasmian käyttäen restriktioentsyymianalyysia sekä kloonausta bakteerisoluihin. Järjestimme potilaiden mtDNA-sekvenssit fylogeneettisiksi puiksi ja kaikki proteiinin koodausta muuttavat geenimuutokset analysoimme haitallisuutta ennus- tavilla tietokoneohjelmilla (SNAP, PolyPhen-2, PMut, SIFT BLink). Diabetesta sairastavilla potilailla, joilla myös äidinpuoleisessa suvussa esiintyy diabetesta, havaitsimme useammin m.3010A>G- ja m.16189T>C-geenimuutoksia kuin väestöllä keskimää- rin. Tutkimustulos tukee aikaisemmin julkaistuja tutkimustuloksia m.16189T>C-geenimuutoksen haitallisuudesta. Epilepsiapotilailta löytyi m.15218A>G-geenimuutos kahdessa U5a1-haploryh- män alatyypissä. Patogeenisyysanalyysien mukaan nämä geenimuutokset olivat haitallisia. Mito- kondriaalinen haploryhmä V havaittiin useammin diabetesta sairastavilla kuin terveillä henkilöil- lä. Tutkimukseen valittiin potilaita, joiden äidinpuoleisilla lähisukulaisilla esiintyi yhtä tai useam- paa seuraavista: diabetes, epilepsia tai aistimistyyppinen kuulovika. Väitöstutkimuksessa todetaan lisäksi, että m.8993T>C-mutaatio aiheuttaa aikuisiällä alkavaa ataksia-oireistoa. Kyseinen mutaatio on aiemmin yhdistetty vain lapsuusiän taudinkuviin. Kuva- simme uuden insertiomutaation (m.7585insT) kardiomyopatiasuvussa sekä uuden MTTT-geenin mutaation (m.15933G>A) tuntematonta mitokondriotautia sairastavalla potilaalla. Väitöskirjatutkimuksen tulokset osoittavat, että on tärkeää tutkia koko mitokondriogenomi, kun kyseessä on tuntemattomaksi jäänyt mitokondriaalinen taudinkuva. Uudet, tautia aiheuttavat, mtD- NA:n geenimuutokset voivat jäädä tunnistamatta, jos tutkitaan ainoastaan raportoidut, tunnetut, mutaatiot. Lisäksi voi todeta, että mitokondriogenomissa esiintyy lievästi haitallisia geenimuutok- sia tai niiden yhdistelmiä, jotka saattavat lisätä riskiä sairastua kansanterveydellisesti merkittäviin sairauksiin, kuten diabetekseen. Asiasanat: aistimistyyppinen kuulovika, ataksia, diabetes, epilepsia, fylogenia, haitallinen polymorfia, mitokondriaalinen DNA, mitokondrio, mitokondriotauti, mtDNA To my Mother 8 Acknowledgements My sincere gratitude goes to my supervisor Kari Majamaa, whose inspiring guidance has made this thesis possible. Thank you for taking me inside the world of mitochondrial genetics and sharing your
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