Human Molecular Genetics, Vol 5, 1417-1423, Copyright © 1996 by Oxford University Press
S Harris, C Moncrieff and K Johnson
The mutation underlying myotonic dystrophy (DM) was identified at the end
of 1991 amidst great rejoicing from the patients supporting the research
and, not least, from those who spent so long searching for it.
Subsequently, the molecular genetic phenomena associated with DM have been
clearly explained by the transmission behaviour of the expanding repeat,
which remains the only mutation that has been described in patients. We
understand the molecular basis of anticipation, why the severe congenital
form is almost exclusively transmitted by affected mothers and we have
widely accepted models of the population genetics of DM. Yet, despite all
these clearly explained molecular events, we appear to be hardly any closer
to understanding the molecular pathology of DM than when the mutation was
first identified. To understand the reason for this, we have to look in
detail at the mutation itself, and in particular at the locus and its
complex nuances. In doing so, we begin to realise that DM is unique amongst
the Mendelianly inherited disorders, in that the mutation, because of its
location in a very gene- rich region of the genome, probably simultaneously
renders several genes dysfunctional. The somatic heterogeneity of the
repeat, coupled with the involvement of several genes, accounts for the
pleiotropy observed in the phenotype. Added to this complexity is the
uncertainty of the level at which gene dysfunction or gain of function is
occurring. It is possibly at the level of DNA/chromatin structure and/or
RNA regulation/processing, and all of these pathways may, in different
tissues, contribute to the final phenotype.
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Myotonic dystrophy: will the real gene please step forward!
Division of Molecular Genetics, IBLS, University of Glasgow, Anderson College, UK.
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