Identification of the molecular key drivers in disease development in myotonic dystrophy type I.

Scriptie/masterproef: Doctoral Thesis


Myotonic dystrophy type I is the most common muscular dytrophy and is
caused by an unstable trinucleotide ‘CTG’ repeat. Due to incomplete
understanding of the repeat behaviour, the disease remains incurable.
With this thesis, I further characterized two main molecular aspects of
the disease being DNA methylation and its role in inheritance of the most
severe forms of the disease and the influence of mismatch repair on
repeat instability.
The disease has different clinical manifestations of which the congenital
form is the most severe with large expansions and almost exclusive
maternal transmission. The molecular factor determining the difference
between the congenital and classical form is unknown. We correlated
methylation in regions flanking the CTG repeat to the most severe forms
of the disease. Almost all congenital patients showed methylation at both
sides of the repeat which is in contrast with no methylation in classical
patients except for the most severe forms. This highlights methylation as
a potential prenatal indicator of the most severe forms of the disease,
including the congenital form, which may guide families faced with an
affected pregnancy.
The mismatch repair machinery and especially its component MSH2 has
been linked to repeat instability due to an incorrect repair creating repeat
expansions. Incomplete understanding of this process is mainly due to
the predominant use of mouse models that do not represent all DM1related
symptoms. This report is the first to study the role of MSH2 in
DM1-affected human pluripotent stem cells, using a MSH2 knock-out
model by CRISPR/Cas9 technology. If the knock out of MSH2 creates
repeat stability or contractions as seen in mouse models, MSH2 could be
used as a drug target to delay disease onset and slow down disease
Datum Prijs28 mrt 2017
Toekennende instantie
  • Vrije Universiteit Brussel
BegeleiderKaren Sermon (Promotor), Hilde Van De Velde (Jury), Thierry VandenDriessche (Jury), Alexander Gheldof (Jury), Rachel Eiges (Jury) & Elfride De Baere (Jury)

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