Mitochondrial DNA variants in early development and ART

Joke Mertens Filippo Zambelli
Analyse van mitochondriale DNA varianten in kinderen geboren na ICSI en spontane verwekking.

Gevarieerder mitochondriaal genoom bij ICSI kinderen

Mitochondria, de energiehuisjes die onze cellen doen ademen. Deze kleine celorganellen hebben hun eigen DNA, ook mtDNA genoemd. Het is ontzettend klein en komt voor in meerdere kopieën per cel. In tegenstelling tot het kern DNA dat je van je beide ouders meekrijgt, wordt het mtDNA enkel door je moeder meegegeven. Het zit in grote hoeveelheden in de eicel voor die bevrucht wordt. Tijdens de ontwikkeling van eicellen verdubbelt het mtDNA talloze keren, dit geeft een hoger risico op het ontstaan van varianten in het mitochondriaal genoom. Varianten zijn DNA-bouwstenen die verschillen van het referentiegenoom. In het kern DNA worden zulke varianten hersteld naar hun oorspronkelijke bouwstenen doordat er een herstelmechanisme aanwezig is. Dit ontbreekt echter voor het mtDNA. Uit onderzoek is gebleken dat de kans op zulke varianten nog hoger wordt als de eicellen tijdens hun ontwikkeling gestimuleerd worden met hormonen, zoals dit gebeurt in IVF en ICSI. IVF, of in vitro fertilisatie (voor vrouwelijke onvruchtbaarheid), en ICSI, of intracytoplasmatische sperma-injectie (voor mannelijke onvruchtbaarheid), zijn technieken die gebruikt worden om koppels die minder vruchtbaar zijn toch de kans te geven om hun kinderwens waar te maken.

Omdat mtDNA in meerdere kopieën per cel voorkomt, kan het ook zijn dat deze kopieën verschillen van elkaar. Wanneer een variant voorkomt in 100% van alle kopieën in de cel, dan is deze variant een homoplasmie. Wanneer een variant echter slechts in enkele kopieën voorkomt, wordt deze variant een heteroplasmie genoemd (zie figuur). Over het algemeen zijn deze homo- en heteroplasmieën goedaardig, maar in bepaalde gevallen kan een variant nadelige gevolgen hebben voor de cel en het organisme.

Maar hoe zit het dan met het mtDNA in kinderen die geboren zijn na IVF en ICSI? Deze kinderen hebben een lager geboortegewicht en een hoger risico op het ontwikkelen van bepaalde aandoeningen. Wat dit veroorzaakt is nog niet geweten, maar mtDNA is wel gelinkt met deze aandoeningen. Daarom vonden onderzoekers aan de Vrije Universiteit Brussel het uiterst interessant om het mtDNA in deze kinderen te onderzoeken op de aanwezigheid van varianten. Ze hebben dit onderzocht door bloedstalen te analyseren van 57 jongvolwassenen die geboren zijn na ICSI en die te vergelijken met 62 jongvolwassen die op natuurlijke wijze verwekt werden. Ook werden de homoplasmieën onderzocht buiten de haplogroep. Haplogroepen bestaan uit een aantal homoplasmieën die tot stand zijn gekomen doorheen de evolutie. Deze haplogroepen zorgden er bijvoorbeeld voor dat mensen uit Afrika efficiënter zuurstof kunnen omzetten in energie zonder al te veel warmte te verliezen, terwijl dit niet het geval is voor bijvoorbeeld mensen uit Noord-Europa, die meer warmte nodig hebben zodat ze kunnen overleven in koudere omgevingen. Je haplogroep beschrijft dus van waar in de wereld je voorouders afkomstig waren. Nu, de homoplasmieën die niet tot je haplogroep behoren zijn vaak ook interessant om te onderzoeken aangezien die pas in de recentere generaties te zien zijn en eigen zijn aan je familie. De onderzoekers vonden dat kinderen geboren na ICSI meer van deze homoplasmieën vertonen die nog niet beschreven zijn in de vakliteratuur. Deze varianten zijn niet per se gevaarlijk maar zijn wel interessant om bijvoorbeeld een mini-evolutie te onderzoeken of om te zien of sommige van deze varianten betrokken zijn bij bepaalde ziektebeelden. Ook de heteroplasmieën werden onderzocht. Deze varianten kunnen dus in een bepaald percentage voorkomen in de cel. Heteroplasmieën zijn moeilijker te analyseren aangezien het niet geweten is hoe belangrijk hun rol is in de cel. De onderzoekers hebben dit opgelost door de verschillende varianten met hun percentages bij elkaar op te tellen. Een voorbeeldje: een cel heeft drie varianten met een voorkomen van 10%, 50% en 90%, dan heeft deze cel een cumulatieve waarde van 150% (dit heet de cumulatieve frequentie) waarin de variant die in 90% voorkomt in de kopieën meer invloed heeft op het metabolisme dan de variant die slechts voorkomt in 10% van de kopieën. Op deze manier zagen de onderzoekers dat er meer kinderen zijn geboren na ICSI met een hogere cumulatieve frequentie dan kinderen die op een natuurlijke manier verwekt werden en dit in de regio’s van het mtDNA die verantwoordelijk zijn voor de aanmaak van eiwitten. Deze eiwitten zorgen voor de omzetting van zuurstof in energie. Kinderen die geboren zijn na ICSI vertonen dus een gevarieerder mitochondriaal genoom maar wat dit betekent moet nog verder onderzocht worden.

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Universiteit of Hogeschool
Master in de Biomedische Wetenschappen
Publicatiejaar
2017
Promotor(en)
Prof. Dr. Claudia Spits
Kernwoorden
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