August 28, 2000
First Bardet-Biedl Syndrome Gene Identified
Researchers have pinpointed a gene mutation that causes Bardet-Biedl
syndrome (BBS), a rare genetic disorder that can lead to mental
retardation.
"BBS is a relatively rare disorder, but it has an interesting
constellation of features, including obesity, mental retardation,
polydactyly [additional digits], genital abnormalities and retinitis
pigmentosa, which can lead to blindness," said Val C. Sheffield of
the Howard Hughes Medical Institute at the University of Iowa. "One
reason we are studying BBS is that it might give insight into obesity
and other common disorders."
“It will be interesting to see if this gene is involved in more common disorders, such as diabetes.”
Val C. Sheffield
The discovery by Anne M. Slavotinek and Leslie G. Biesecker at the
National Human Genome Research Institutes, Sheffield and colleagues at
the University of Iowa and a number of other institutions is reported
in the September 2000 issue of the journal Nature Genetics.
Particularly interesting about BBS, said Sheffield, is that it
arises from defects in at least six different genetic loci (regions of
chromosomes). "When we first began to study BBS, our hypothesis was
that it was an autosomal recessive, single locus disorder," said
Sheffield. "We had found an inbred population of Bedouins in Israel
with BBS and mapped the gene to a locus on human chromosome sixteen. We
then identified a second Bedouin population with the disease, and found
that their affected gene didn't map to same location. This gave us the
first clue that there was genetic heterogeneity in people with
BBS."
Sheffield and his colleagues first zeroed in on the newly discovered
BBS gene, called MKKS, because Biesecker and his colleagues had
established that it caused McKusick-Kaufman syndrome (MKS) in a large
Amish population. "The one phenotypic feature shared by people with BBS
and MKS is extra digits," said Sheffield. There was also evidence that
there may be a BBS locus on chromosome twenty, where the MKKS
gene resides. "So, we screened the MKKS gene for mutation in BBS
families whose disease showed no evidence of linking to any of the
other known loci," he said.
The screening revealed that four of the 34 people with BBS had
mutations in the MKKS gene. Importantly, said Sheffield, the
mutations in MKKS were of the type that completely knocked out
the gene's function, leading the scientists to hypothesize that MKS
might be due to a crippled form of the MKKS gene, whereas BBS is
caused by a complete knockout of the gene.
According to Sheffield, the finding of the nonfunctional MKKS
gene in a relatively small group of people with BBS hints that the gene
is, indeed, a cause of the disorder. "It's pretty much what we
expected," he said. "You would expect that the majority of the disease
in those families would be caused by defects at one of the other five
loci. We expected only about ten percent of families to be accounted
for by the MKKS gene."
According to Sheffield, the discovery of the role of MKKS in BBS
will likely help pry open other secrets of the disease. "We're
interested in using this as a clue, hopefully, to finding the other BBS
genes," he said. According to Sheffield, the protein produced by the
MKKS gene is likely to be a common part of a metabolic pathway
that is altered to produce the constellation of abnormalities seen in
BBS patients.
While the protein product of the MKKS gene is still unknown,
he said, the gene has a similar sequence to other genes that produce
chaperonins, proteins that aid in the proper folding of newly
synthesized proteins.
Discovering the role of MKKS in BBS might also lead to
insights into other more common diseases, said Sheffield. "We are
intrigued that these BBS families have a high incidence of diabetes,"
he said. "So, it will be interesting to see if this gene is involved in
some of these more common disorders. While that is unlikely, I think
that studying the MKKS protein, and the protein it interacts with, may
lead us to pathways or to complex structures that may play a role in
more common diseases such as diabetes."
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