Researchers at Johns Hopkins have discovered that two
clinically different inherited
syndromes are, in fact, variations of the same disorder.
Reporting in the April issue of Nature
Genetics, the team suggests that at least for this
class of disorders, the total number and "strength"
of genetic alterations an individual carries throughout the
genome can generate a range of symptoms
wide enough to appear like different conditions.
"We're finally beginning to blur the boundaries
encompassing some of these diseases by showing
that they share the same molecular underpinnings," said
Nicholas Katsanis, an associate professor of
ophthalmology at the
McKusick-Nathans Institute of Genetic Medicine at Johns
Hopkins. "This is
important progress for several reasons. First, knowing
what's going on molecularly and being able to
integrate rarer conditions under common mechanisms allows
us to potentially help more people at once.
Second, clinicians can finally begin to offer more accurate
diagnoses based on what really matters: the
state of affairs at the cellular/biochemical level. In
time, this will empower genetic counseling and
much improved patient management."
Katsanis' team studies Bardet-Biedl syndrome, or BBS,
a rare so-called ciliopathy that is
characterized by a combination of vision loss, obesity,
diabetes, extra digits and mental defects and is
caused by faulty cilia, tiny hairlike projections found on
almost every cell of the body. Recently they
started looking at another disease, Meckel-Gruber syndrome,
or MKS, which also shows cilia
dysfunction but is clinically distinct from BBS and is
generally associated with prenatal or newborn
"While these two groups of patients exhibit such
different clinical outcomes, the genes
associated with both syndromes all seemed to be pointing at
the same culprit: cilia," Katsanis said. "So
we wondered if BBS and MKS might actually represent
different flavors of the same disease."
The researchers sequenced the MKS genes from 200 BBS
patients and found six families that,
in addition to carrying BBS genetic mutations, also carried
mutations in MKS genes. To figure out
what, if any, effect these MKS mutations have on BBS, the
team used a system they previously
developed in zebra-fish.
Knocking out BBS genes in zebrafish generates short
fish with even shorter tails, among other
malformations. Injecting normal BBS genes into these fish
rescues them, resulting in normal-looking
The researchers reasoned that if MKS and BBS are
indeed the same condition, then fish with
the MKS genes knocked out should mimic the BBS knockout
fish. They did. The team then went on to
test mutant versions of MKS genes in BBS fish and found
that three genes originally attributed to
MKS do indeed cause BBS or render the BBS defects more
pronounced, increasing the number of BBS
genes to 14 in total.
"From a clinical perspective, these two syndromes look
nothing alike, but molecularly, the genes
involved clearly participate in the same fundamental
processes," Katsanis said. "This means that
Meckel-Gruber and Bardet-Biedl actually represent a
continuum of one disease. This never would have
been discovered in the clinic; only molecular analysis can
reveal these things."
But what does this mean for clinicians and the
diagnosis and treatment of these syndromes?
Katsanis said he hopes that the growing body of molecular
data will help move medicine away from
symptom-defined syndromes, which can leave clinicians
struggling with ambiguous diagnoses, to
approaching disorders from a molecular standpoint.
"We now have the possibility of merging several rare
disorders," he said. "And their gross sum
now turns out to be fairly common; hopefully this will now
put them on the radar for drug development
and other therapies."
The research was funded by the National Institutes of
Health; National Institute of Child
Health and Development; National Institute of Diabetes,
Digestive and Kidney Disorders; Polycystic
Kidney Disease Foundation; Medical Research Council;
Research to Prevent Blindness; and Wellcome
Authors on the paper are Carmen Leitch, Norann
Zaghloul, Erica Davis and Katsanis, all of Johns
Hopkins; Corrine Stoetzel and Helene Dollfus, Universite
Louis Pasteur, Strasbourg, France; Anna
Diaz-Font, Suzanne Rix and Philip Beales, University
College London, U.K.; Majid Al-Fadhel and Wafaa
Eyaid, King Fahad Hospital, Riyadh, Saudi Arabia; Richard
Alan Lewis, Baylor College of Medicine; Eyal
Banin, Hadassah-Hebrew University Hospital, Jerusalem; and
Jose Badano, previously of Johns
Hopkins and now at the Institut Pasteur de Montevideo,