Transcript Myotonic dystrophy DM

Myotonic dystrophy
DM
Suhail Abdulla AlRukn
19-03-2008
Outline
- Overview of repeat expansion disorders.
- Introduction to DM
- Etiology and pathophysiology of DM
- Model mechanisms for myotonic dystrophy:
- Haploinsufficiency of DMPK
- Haploinsufficiency of SIX5 and neighboring
genes
- RNA pathogenesis
Learning Objective
-Introduction to repeat expansion disorders
and the different between the unstable
expanding repeats in noncoding regions and
ustable expanding repeats in coding regions.
-The pathophysiology of DM, and the three
model mechanisms for myotonic dystrophy.
Overview of repeat
expansion disorders
-There are more than 30 neurological
disorders that can attribute their pathogenesis
to extensions of tandem repeats above a
critical size.
-Yet the theories as to how large repeat arrays
can cause such highly variable diseases are
unresolved.
Overview of repeat
expansion disorders
-Most of the expansion disorders exhibit a
delayed onset form of their diseases, indicating
that they may share mechanisms that postpone
clinical expression until later in life.
-Depending on where the unstable repeats are
located within the gene, the repeat expansion
disorders can be classified as having coding or
noncoding mutations.
Overview of repeat
expansion disorders
-Coincidentally, in 1991, the first two triplet repeat
expansion disorders discovered revealed examples
from both coding and noncoding categories:
-The fragile X syndrome was linked to unstable
CGG repeats in the noncoding 5′UTR of FMR1.
-Whereas spinobulbar muscular atrophy was
associated with unstable coding CAG repeats.
Overview of repeat
expansion disorders
- DM1 followed in 1992 as the third trinucleotide
repeat expansion disorder discovered and was mapped
to CTG repeats in the noncoding 3′UTR of DMPK.
-UREDs can be divided into two major classes:
-Unstable expanding repeats in noncoding regions.
-Unstable expanding repeats in coding regions.
Unstable expanding repeats in noncoding
regions.
Biochim Biophys Acta. 2007 Feb;1772(2):195-204. Epub 2006 Jun 20.
Unstable expanding repeats in coding regions.
Biochim Biophys Acta. 2007 Feb;1772(2):195-204. Epub 2006 Jun 20.
Introduction
-Myotonic dystrophy (DM) is the most
common muscular dystrophy in adults, and is
the second most common muscular dystrophy
after Duchenne muscular dystrophy.
-Onset is usually in the second or third
decade.
-The prevalence of DM is 1 in 8000 in the
general population
The clinical signs of classical
myotonic dystrophy
Netter, F.H. The CIBA collection of Medical Illustrations. 1986
Types
• The genetic causes of three forms of DM
have been identified:
– DM1, also known as Steinert's disease
– DM2, also known as proximal myotonic
myopathy (PROMM) 1994
– Congenital myotonic dystrophy (CMyD)
POPULATION GENETICS
-In the Saguenay region of
the province of Quebec, the
prevalence of DM is about 1
in 475; about 600 cases are
known in a population of
285,000.
-The prevalence of myotonic
dystrophy is 30 to 60 times
higher than the prevalence
in most other regions of the
world. (1/475 Vs 1/25,00).
Etiology
-DM is autosomal dominant disease.
-DM1 results from an unstable trinucleotide repeat
expansion, CTG, in the 3' non-coding region
(myotonic dystrophy type-1 protein kinase, DMPK)
on chromosome 19q13.3.
- DM2 results from an unstable tetranucleotide
(CCTG) repeat expansion in the intron 1 of ZNF9 on
chromosome 3q21.
Etiology
Source: Science (2001) 293:816-817.
Etiology
-The cause of the unstable CTG repeat
expansion is unknown; however, it is thought to
occur during gametogenesis and is more
extensive when coming from a female carrier.
- The disease severity generally correlates with
repeat length.
Source: Science (2001) 293:816-817.
Model mechanisms for
myotonic dystrophy
1)Haploinsufficiency of DMPK
2)Haploinsufficiency of SIX5 and neighboring
genes
3)RNA pathogenesis
RNA toxic gain-of-function model for myotonic dystrophy
Biochim Biophys Acta. 2007 Feb;1772(2):195-204. Epub 2006 Jun 20.
Haploinsufficiency of DMPK
-Early expression studies were consistent
with the hypothesis that the mutation
interfered with DMPK production, in that
mRNA and protein levels were reduced in
patient muscle and cell culture.
-However, DMPK knockout mice showed
only a very mild, late-onset myopathy
without the multisystemic features of the
disease.
Haploinsufficiency of DMPK
-The fact that no DMPK point mutations
have been associated with a DM
phenotype further suggests that the
multisystemic features of DM1 are not
simply caused by DMPK
haploinsufficiency.
Haploinsufficiency of SIX5 and
neighboring genes
-A second proposed mechanism has been that the
mutation interferes with expression of multiple genes in
the DM1 region, possibly through regional effects
produced by repeat-induced alterations in chromatin
structure.
-In addition to DMPK and the neighboring
homeodomain gene SIX5, other regional genes suggested
to be involved in DM1 pathogenesis have included
myotonic dystrophy gene with WD repeats, DMWD,
which is prominently expressed in the testis and brain.
Haploinsufficiency of SIX5 and
neighboring genes
-In this model, the multisystemic features of DM1
would be explained by haploinsufficiency of a number
of neighboring genes, with expression level and hence
disease severity, dependent on repeat length.
-In support of this possibility, Six5 knockout mice
develop cataracts, but without the posterior
subcapsular location or the distinctive opacities that
are characteristic of cataracts in DM patients.
RNA pathogenesis
-A third hypothesized mechanism is that the
enlarged CUG-containing transcripts accumulate
as intranuclear foci and disrupt cellular function.
-Direct support for this model came from a
transgenic mouse model, in which the CTG
expansion was inserted into the 30 end of the
human skeletal actin gene, a gene not directly
involved in DM1 but which is expressed only in
skeletal muscle.
RNA pathogenesis
-This mouse model expressed an mRNA with a
CUG repeat tract of 250 repeats, and caused the
myotonia and myopathic features characteristic of
DM1.
-But because CUG-containing transgene
expression was limited to skeletal muscle the role
of the CUG expansion in the multisystemic
features of DM was not addressed.
RNA toxic gain-of-function model for myotonic dystrophy
Biochim Biophys Acta. 2007 Feb;1772(2):195-204. Epub 2006 Jun 20.
Pathogenic model of DM1 and DM2.
Muscle histology in DM2
Home Take massage
- The severity of the URED’s correlates with repeat
length
- DM1 results from an unstable trinucleotide repeat
expansion, CTG, DMPK on chromosome 19q13.3.
- DM2 results from an unstable tetranucleotide
(CCTG) repeat expansion in the intron 1 of ZNF9 on
chromosome 3q21.
- The cause of the unstable CTG repeat
expansion is unclear but there are few model
mechanisms.
Thanks