Rajalaxmi Natarajan, Ph.D.
Oct 5, 2017
collaborative study published in PLoS Genetics has already
helped physicians determine a unique treatment plan for an ataxia
patient carrying a novel, toxic, gain-of function mutation in a
calcium channel gene. This exciting discovery could
potentially become a standard paradigm for treating such patients
in the future.
The research surrounding this gene, which is the cause of
premature neurodegeneration and muscular incoordination in a young
ataxia patients, was conducted in the laboratory of
Dr. Michael Wangler at the
Jan and Dan Duncan Neurological Research Institute at Texas Children's
Hospital and Baylor College of Medicine.
In this study, physicians and scientists studied a group of five
patients with severe early-onset motor incoordination, global
developmental and speech delays. Previously, it had been reported
that patients with missense variations in the calcium channel gene,
CACNA1A, also exhibited similar symptoms. Studies in
animal models showed that loss-of-function of cacophony
(cac), a gene that encodes for a voltage-gated calcium
channel, which transports calcium ions into cells, could be the
cause of these clinical symptoms.
Interestingly, in addition to motor and speech deficits, one of
the five patients in this study (referred as Patient 1), also
exhibited progressive degeneration of the cerebellum, which was not
present in the other four patients. Whole exome sequencing of all
the five patients and their parents showed that Patient 1 carried a
completely different kind of mutation in
To study the functional consequences of this unique variant to
neuronal function, researchers in the Wangler lab generated
transgenic fruit flies that carried this missense human variant
instead of the normal fruit fly version of
They showed that this toxic gain-of-function mutation was
responsible for the massive influx of calcium ions into the neurons
of fruit flies, causing damage and destruction. The authors
concluded that this mutation is likely also the cause of
progressive degeneration of cerebellar neurons observed in Patient
Responsiveness to a treatment or medication depends on the
specific nature of the genetic defect that is being corrected.
Typically, patients with loss of calcium channel function respond
to acetazolamide to activate calcium channels. As a result of
identifying that Patient 1 carries a novel gain-of-function
mutation, physicians were able to switch the medication regimen to
a drug that blocks calcium channel function.
Researchers are hopeful this study will equip physicians with
the knowledge needed to identify the exact mutation in calcium channel gene responsible for ataxia and other symptoms in patients, which will then allow physicians to offer personalized treatment plans.