Pn. Strong et Bs. Brewster, MYOTONIC-DYSTROPHY - MOLECULAR AND CELLULAR CONSEQUENCES OF EXPANDED DNA REPEATS ARE ELUSIVE, Journal of inherited metabolic disease, 20(2), 1997, pp. 159-170
The mutation in the myotonic dystrophy (DM) gene is an expansion in a
triplet (CTG)(n) repeat in the 3' untranslated region of a novel gene
that partially encodes a serine-threonine protein kinase (DMPK), with
closest sequence homology to a small subgroup of protein kinases invol
ved in the control of proliferation and cell shape. Expansion of the r
epeat correlates reasonably well with disease severity and offers a pl
ausible molecular explanation for the previously contentious issue of
anticipation. There is considerable heterogeneity in CTG expansion siz
e in different tissues of affected individuals. The consensus of data
from many laboratories indicates that DMPK mRNA is most probably downr
egulated as a consequence of the repeat expansion. Two polypeptides (6
8/78 kDa) have been shown to be absent in mouse knockout mutants and t
herefore can be considered as bona fide products. Previous data sugges
ting that 52-55 kDa polypeptides were likely candidates, have been fir
mly ruled out at the same time. Further results from studies of knocko
ut and overexpressing transgenic mice indicate that neither simple los
s nor gain of DMPK expression is sufficient to account for the DM clin
ical phenotype. One of the most pressing questions now being addressed
is how expansion of the CTG repeat within the DMPK gene affects gene
expression, not only of DMPK, but of all genes at the 19q13.3 locus: i
s DMPK actually responsible for the clinical phenotype seen in DM? The
identification of both immediate upstream and downstream human genes
(59 and DMRHP, respectively) has been an important first step to answe
ring these questions. Only when these matters have been dealt with can
one reasonably expect to start to delineate the different metabolic a
nd signalling pathways responsible for the diverse phenotypes that mak
e up the complex clinical picture of DM.