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After an arduous 10-year search, scientists have found a genetic mutation
that appears to be the cause of Huntington’s disease, a devastating neurodegenerative
illness that usually starts in middle age and ultimately leads to wild movements
of the limbs, mental deterioration and death. Identification of the gene
responsible for Huntington’s will solve a number of mysteries surrounding
the genetics of the disease and allow better screening to identify children
who have inherited it.

In 1983, researchers traced the gene to somewhere near the end of chromosome
4, although at the time they had no idea about the identity or function
of the gene. A decade later, in this week’s issue of the journal Cell, an
international collaboration of six laboratories has announced the discovery
of the gene. All six laboratories contributed to what Hans Lehrach of the
Imperial Cancer Research Fund, a member of the group, calls a ‘tremendous
scientific detective story’.

The gene was finally isolated in James Gusella’s laboratory at the Massachusetts
General Hospital by a team headed by Marcy McDonald. The author of the paper
is given as the Huntington’s Disease Collaborative Research Group. In addition
to the laboratories at Massachusetts General and the ICRF, the group includes
teams from the Massachusetts Institute of Technology, the University of
California at Irvine, the University of Michigan and the University of
Wales College of Medicine.

The Huntington’s disease mutation turns out to be an unstable segment
in the DNA of a previously unknown gene that codes for a protein the group
named ‘huntingtin’. They labelled the gene IT15, for ‘interesting transcript
number 15′. In people without the disease, the segment is made up of between
11 and 34 repeats of the triplet C-A-G (the bases cytosine-adenine-guanine).
In 75 families affected by Huntington’s disease, individuals with the disease
had between 42 and 100 repetitions.

In the past two years, researchers have found similar ‘stuttering’ triplets
to be the cause of other genetic diseases, including fragile X syndrome,
myotonic dystrophy, and spino-bulbar muscular atrophy. In the case of Huntington’s
disease, the researchers found a rough correlation between the number of
times the triplet repeated and the age at which the disease began to take
hold. The more copies of the triplet, the earlier the disease began. Some
of the longest repeating sequences came from a huge extended family in Venezuela,
in which the disease sometimes strikes children.

The collaboration had been in fierce competition with two other groups
to find the gene. There was a moment of high drama last week when the researchers
learnt that a paper by Michael Hayden of the University of British Columbia
was to be published in the journal Nature a day before their own report.

In his paper, Hayden describes a ‘strong candidate’ for the Huntington’s
gene. His team found a transposable element or ‘jumping gene’ that seemed
to be associated with Huntington’s disease in two people. However, the genetic
rearrangement was not found in 248 other Huntington’s patients.

Hayden conceded late last week that the collaboration had found the
Huntington’s gene. ‘This is fantastic news for patients,’ he said. ‘It should
dramatically improve diagnosis of the disease.’ Both Hayden and the third
team searching for the gene, led by Richard Myers and David Cox of the University
of California at San Francisco, vowed to continue working on the genetics
of Huntington’s disease. ‘A new race is starting now, the race to understand
how the mutation causes the disease.’ says Myers.’