Early-onset torsion dystonia (DYT1) is a
dominantly inherited movement disorder with affected individuals
developing sustained, involuntary muscle contractions
and abnormal, twisted posturing. Symptoms result from
abnormal functioning of the basal ganglia, but with no
apparent neuronal degeneration. Patients are otherwise
medically normal with normal-to-high intelligence. Almost
all cases of early-onset torsion dystonia are caused by
the same mutation, a GAG deletion in the 3' coding region
of the message, resulting in deletion of a glutamic acid
near the C terminal. The high frequency of this mutation
in the Ashkenazic Jewish population is due to a pogrom
in Lithuania 350 years ago (a cruel twist of fate).
The novel protein responsible for the disease,
torsiriA is a member of a family of proteins called AAA
- ATPases associated with a variety of cellular activities.
AAA-family proteins are the sumo wrestlers of proteins,
because they pull or twist protein interactions apart.
TorsinA is expressed in all cells, with high levels in
neurons in certain regions of the brain. Within cells
it is localized predominantly in the lumen of the endoplasmic
reticulum-a processing center for membrane-secreted proteins
that twists its way around the nucleus and throughout
the cytoplasm. TorsinA is involved in connecting the nuclear
envelope and endoplasmic reticulum with the cytoskeletal
network. The loss of torsinA or its mutant form contort
the integrity of the nuclear envelope and the dynamics
of the endoplasmic reticulum (neurite extension and synaptic
integrity).
