Research Review No. 82.
An interesting Mutation in the Dystrophin Gene.
A recent review.
Introduction:
Duchenne Muscular Dystrophy (DMD) has been clearly demonstrated
over the last years to be the result of a mutation in the Dystrophin gene, causing
the Dystrophin protein to be lacking in the muscle cells of the affected person.
Generally in these mutations there is a deletion or duplication of part of the
Dystrophin gene causing a frame-shift in the reading frame causing the gene to
be completely misread and producing nonsense. If the mutation stays in-frame
the frequent outcome is the milder version of DMD, namely Becker Muscular
Dystrophy (BMD). There are other mutations that also cause a loss of production
of Dystrophin, but these are not relevant to this discussion. The paper being
discussed (1) described a very unusual mutation, which may be of interest to
those involved with DMD or BMD.
The Study:
This study mainly from the Netherlands, but other European countries
were involved, identified an unusual mutation in the Dystrophin gene of a family
with nonspecific X-linked intellectual disability. To remind readers, the Dystrophin
gene is on the X-chromosome, and males have only one X-chromosome and
females have two. This is why DMD affects males far more frequently than
females.
This study of a family with nonspecific X-linked intellectual disability
identified a deletion of three base pairs, thus a single triplet of the genetic code,
in the Dystrophin gene. The mutation was therefore ‘in-frame’. The authors of this
study found that this in-frame deletion resulted in the deletion of a single-aminoacid residue, Leucine, Leu3238.
The Dystrophin gene not only codes for Dystrophin, which has a major
function in the maintenance of the integrity of the muscle cells but parts of it code
for other proteins, which are known as isoforms of Dystrophin. Some of these
isoforms have a function in brain cells. Thus the loss of the amino-acid leucine
from the brain-specific isoform Dp71 appears to affect the function of this isoform
and leads to the intellectual disability found in these patients.
Molecular modeling studies, which are illustrated predict that this specific
deletion of the amino acid leucine results in the destabilization of part of
Dystrophin and hence reduces the ability to interact with -dystroglycan, which
does not affect the cellualar function of Dystrophin. They conclude by stating
that: “we have identified the first DMD mutation in Dp71 that results in
[intellectual disability] ID without muscular dystrophy”.
References:
1.
Brouwer, A.P.M., Nabuurs, S.B., Verhaart, I.E.C., Oudakker, A.R., Hordijk,
R., Yntema, H.G., Hordijk-Hos, J.M., Voesenek, K., de Vries, B.B.A., van Essen,
T., Chen, W., Hu, H., Chelly, J., den Dunnen, J.T., Kalscheuer, V.M., AartsmaRus, A.M., Hamel, B.C.J., van Bokhoven, H. & Kleefstra, T. (2014) A 3-base pair
deletion, c.9711_9713del, in DMD results in intellectual disability without
muscular dystrophy. European Journal of Human Genetics. 22(4):480-485.
Karl A. Bettelheim
1.5.2014