DMD Flashcards
DMD is a
Sex-linked disorder that has almost complete penetrance in males
Mutant DMD gene found at position
X21.2-22.1
DMD gene is regulated by
Three 5’ promoters and four internal promoters
DMD is a rod shaped protein with
4 functional domains that is crucial for stabilisation of the sarcolemma (Muntoni et al., 2003)
Hinge region interrupting the 24-spectrin-like repearts in the rod domain provide
elasticity to the protein (Gao et al., 2015)
Associated proteins in the cysteine-rich domain and carboxyl-terminus domain allow
Protein to form the dystrophin-associated glycoprotein (DAG) complex
DAG complex is vital for
Maintaining muscle integrity
Stabilisation is mediated by the DAG complex which directly
Links the basal lamina of the extracellular matrix to the cytoskeleton of the muscle
Dystrophin acts as a
Chain that links the skeleton of the myocyte to the extracellular matrix
LoF leads to
destabilisation of muscle membrane which results in excess influx of calcium into skeletal and cardiac muscle cells due to hypercontracted muscle fibres and membranes
Excessive calcium influx activates proteases within the muscle that..
further potentiates calcium influx causing apoptosis, necrosis and muscle degeneration
Mutations in DMD have ..
Pleiotropic effect
affect CV and respiratory systems
Initial symptoms of patients with DMD are
Waddling gait and difficulty climbing stairs (evident between 2-5 years of age)
delayed developmental milestones (Blake et al., 2002)
and Gower’s sign
Gower’s sign
child uses arms to climb up their body in order to assume standing position from laying down
characterised by pelvic girdle weakness
Elevated levels of creatine kinase in blood serum which is produced in
damaged muscle
over 4000 mutations in DMD have been found
Blake et al 2002
Intragenic deletions account for
60-65% of mutations causing DMD (Tayeb 2010)
Exonic deletions can occur
anywhere in the gene
Mutational hotspots at
5’ end of the gene and in the distal region
Gao 2015
Result of LoF of dystrophin protein and severity of disease is dependent on..
how the mutations affect the reading frame of the protein
More than 90% of deletion mutations in DMD
disrupt the reading frame of the protein causing a frame-shift
Frame-shift causes
Generation of a stop codon ending translation resulting in a truncated and unstable protein and in some cases dystrophin is not produced
(Gao and McNally, 2015)
