A genetic study at UCL Institute of Neurology
has identified the gene responsible for a rare form of dystonia called
‘hereditary whispering dysphonia’ or DYT4. The study found that a
mutation in the autoregulatory
domain of the β-tubulin 4a gene (TUBB4a) is responsible for this
disease which is known to affect a large family who emigrated to
Australia from the UK in the late 19th century.
This unusual form of dystonia is characterised
by a progressive limb and cervical dystonia together with a severe
dysphonia which resulted in most of the affected individuals being
unable to speak and who exhibited
an unusual ‘hobby horse’ gait. This was first reported by the late
Neville Parker in 1985 who instigated a collaboration with Anita Harding
to try to identify the genetic cause of this disease in this family.
Using the exome sequencing platform at ION together
with a robust genetic linkage study, a team led by Prof Henry Houlden
has identified the causative gene, with the results now published in the
Annals of Neurology.
The mutation is located within a very small
region of the TUBB4a protein that is important in auto-regulating the
levels of TUBB4a mRNA. As part of previous work published in 1988 in
Nature, it was shown that mutations
in this region result in a loss of this autoregulatory function. This
disease mechanism has not hitherto been reported and provides further
insight into the pathogenesis of dystonia in general.
http://onlinelibrary.wiley.com/doi/10.1002/ana.23832/abstract