Johns Hopkins scientists studying a rare inherited
syndrome marked by eye and kidney problems, learning
disabilities and obesity have discovered a genetic mutation
that makes the syndrome more severe but that alone doesn't
cause it. Their report appears in the Dec. 4 advance online
edition of Nature.
The new discovery about Bardet-Beidl syndrome came
from a panoply of studies — starting with comparative
genomics and experiments with yeast, and moving to
experiments with zebrafish and genetic analysis of families
with the syndrome — and mirrors what experts expect
for the genetically complex common diseases that kill most
Americans, like diabetes, heart disease and cancer.
"Scientists are going to have to think very hard
before they discount genetic variation that appears not to
directly cause a disease," said the study's leader,
Nicholas Katsanis, associate professor in the
McKusick-Nathans Institute of Genetic Medicine at Johns
Hopkins. "The onus is on us to figure out how to
dissect the effects of what appear to be silent genetic
variants. I have a greatly renewed respect for the
complexity of the genome, for the subtle ways that genes
and gene products interact with each other."
Conventional wisdom says that a collection of subtle
genetic variations contributes to a person's risk of common
diseases, but hunting for such subtle effects is daunting.
As a result, most gene hunts have targeted relatively rare
diseases that appear from their pattern in families to be
fairly simple genetically.
Katsanis and his colleagues have recognized for years
that Bardet-Beidl syndrome, although rare, is more similar
to the genetic complexity of common diseases, in part
because patients with this condition have extremely
variable severity, even within families. The newly
identified mutation, in a gene called MGC1203, is the first
to affect only the severity of the syndrome. Mutations in
eight other genes, all dubbed BBS genes, are known to cause
the disease, often in combination with each other.
The identification of MGC1203's role in BBS stems from
the researchers' earlier discovery that disease-causing
mutations in the BBS genes disrupt the function of cilia,
tiny structures that can act like antennae on cells (in the
eye and brain, for instance), help cells move (e.g., in
sperm) or help move fluid around cells (in the lung and
brain, for example).
To build on this finding, Katsanis and his team
combined results from two data-rich experiments. In one,
Katsanis and members of his lab used yeast to identify
proteins that interacted with the yeast's BBS proteins; 60
turned up in their first round of experiments. In the
other, reported last year, a large research team compared
the genomes of various species to identify genes involved
in the function of cilia; more than 600 were found.
But by identifying which turned up in both sets of
results, the researchers narrowed down the hunt to just one
Using standard tools of biology, the Johns Hopkins
researchers determined that the MGC1203 protein is found in
the same part of the cell as BBS proteins and that the
MGC1203 and BBS proteins interact. Furthermore, by studying
the genes of families with BBS, they also discovered that
the most severely affected individuals have a single
mutation in their MGC1203 gene. And zebrafish carrying
mutations in both MGC1203 and BBS genes had more severe
problems than zebrafish carrying only BBS gene
At first glance, the mutation appears not to affect
the sequence of the MGC1203 protein, a finding that stumped
Katsanis. But because so much evidence pointed to a role
for this mutation in the disease, Katsanis and postdoctoral
fellow Jose Badano kept searching.
Their perseverance paid off. Like other genes, the
MGC1203 gene is made of DNA, and its message is transcribed
into DNA's cousin, RNA. The RNA, in turn, can be cut apart
and put back together in various ways and then "read" to
build a protein, much like raw video footage can be edited
to make different movies.
For MGC1203, two different RNA messages are normally
produced, one that is used to make protein and one that is
destroyed by the cell, the researchers discovered with help
from the Howard Hughes Medical Institute laboratory of
Hopkins researcher Harry Dietz.
Badano and Katsanis then discovered that the genetic
mutation in MGC1203 shifts the normal balance of the two
RNA messages, increasing the amount of the destroyed
message produced. That shift alone seems to be the problem,
said Katsanis, who is now studying how it affects the
biology of cells.
"Everyone's cells make both messages, but people with
the BBS-associated mutation make more of the version that
the cell destroys right away," said Katsanis, whose
laboratory also is studying the MGC1203 protein's exact
role in cells. "Somehow, this exacerbates the effects of
mutations in the BBS genes."
Katsanis said that he suspects the human genome
contains thousands of variants with similarly subtle
effects that contribute to complex genetic diseases like
obesity, diabetes and hypertension.
The Johns Hopkins researchers were funded by the
National Institute of Child Health and Human Development;
National Institute of Diabetes, Digestive and Kidney
Diseases; National Institute for Arthritis and
Musculoskeletal Diseases; Polycystic Kidney Disease
Foundation; and Howard Hughes Medical Institute.
Authors on the paper are Jose Badano, Carmen Lietch,
Stephen Ansley, Shaneka Lawson, Harry Dietz, Shannon Fisher
and Nicolas Katsanis, all of the McKusick-Nathans Institute
of Genetic Medicine at Johns Hopkins; Helen May-Simera and
Philip Beales, University College London; and Richard
Lewis, Baylor College of Medicine.