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Detective work identifies damaged
vision-related gene for extended family
Dogged detective work by researchers and clinicians has helped to identify
a vision-related gene that has troubled a large Ma-ori family for at least five
generations.
Dr Marion Maw, a molecular geneticist from the Biochemistry Department,
University of Otago says the genetic disorder usually manifests itself as poor
vision in both males and females from the family. The vision impairment is
most severe in affected male family members, some of whom may also have
intellectual disabilities and autism.
The condition was noticed in the 1990s by Auckland ophthalmologist Dr
Carolyn Hope, who realised the symptoms didn’t fit any known disorders.
An HRC seeding grant was used by Dr Hope and a family member to begin
the task of tracing the family history of the condition. They found it went
back more than a century.
Working in partnership with the family, Dr Hope began a detailed clinical
characterisation of the disorder. Further investigation by her colleague
Dr Dianne Sharp identified poor transmission of electrical signals from the
light-sensing cells of the retina, the tissue at the back of the eye that converts
light into nerve signals to the brain.
Dr Maw and her team were asked to investigate the genetic links. What
they uncovered was an extremely rare genetic condition, possibly the result
of a spontaneous mutation in a female ancestor that resulted in some of her
children being affected by profoundly poor vision, despite having different
fathers.
The genetic work was initiated by Ma-ori Summer Research Scholarship
student Ariana Hemara-Wahanui. She then embarked on an MSc in which
she isolated a defective calcium channel gene involved in a pathway which
sends signals from the light-sensing cells of the retina to the brain.
In the healthy eye, the entry of calcium into light-sensing cells is tightly
regulated, as part of the signalling pathway, but in the case of this subtle
mutation it is likely that too much calcium is able to enter, Dr Maw explains.
“Austrian collaborators found that the subtle alteration causes the calcium
channel to open more easily and to shut more slowly,” she says.
“The retinal light-sensing cells are able to detect the light stimuli but they
are not being correctly converted into nerve signals to the brain because the
calcium channel is behaving inappropriately, and that leads to impaired
vision.”
Researchers have now widened their focus to the connection between the
defective gene and intellectual disability and autism.
Dr Maw says it seems the damaged calcium channel is involved in the brain
dysfunction but just how and where needs further research.
The best way to do this is through a mouse model they are developing so
they can look for changes in brain function in mice with the same genetic
disorder.
This research has received funding from the Health Research Council, Lottery Grants
Board, the Maurice and Phyllis Paykel Trust, several Ma-ori trust boards, Retina
Australia, the University of Otago, and the Ministry of Science, Research and
Technology.
HRC67 2006
Level 3, 110 Stanley Street, Auckland PO Box 5541,
Wellesley Street, Auckland, NZ
Telephone 64 9 303 5200 Facsimile 64 9 377 9988
Website www.hrc.govt.nz
Health Research Council of New Zealand
Te Kaunihera Rangahau Hauora o Aotearoa
Dr Marion Maw
Key words:
– calcium channel mutation,
inherited retinal disorder.
Key facts:
– the inherited genetic disorder
identified by this research has
been traced back over at least five
generations.
Aims of this research:
– to further understand the effects
of a subtle alteration in a calcium
channel gene
– to develop a mouse model to
understand how the gene is
causing autism and intellectual
disability and eventually look
at treatment options such as
established calcium channel
blockers.
What the research has found:
– that while family members
affected by the condition had
retinas that appeared normal, the
electrical signalling within the
retina was dysfunctional
– the impaired electrical signalling
was caused by an extremely rare
genetic condition
– the mutation causes the calcium
channel to be hyperactive
affecting the way light
stimuli is converted into
signals to the brain.