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Rare disease reveals clues about genetic inheritance

by Ruth SoRelle, MPH

Richard Lewis, MD, MS

In the nearly two decades that Richard Lewis, MD, MS, has been studying Bardet-Biedl syndrome, at least eight genes associated with the disease have been found. In the meantime, he and his colleagues – among them James Lupski, MD, PhD, at Baylor College of Medicine in Houston, have discovered oddities about this disease that have changed the way inheritance of diseases are viewed and uncovered hitherto unexpected answers about common problems – all of them linked to this rare genetic phenomenon.

“I am fascinated by the incredible variety of the human organism,” said Lewis, a professor of ophthalmology, medicine, pediatrics and molecular and human genetics at Baylor. “We have to learn what is abnormal first before we figure out what’s normal. What are these kids and adults teaching us about who we are as humans and what makes us normal?”

Bardet-Biedl syndrome is characterized by obesity, disorder of the retina, the portion of the eye in which visions resides; mental and growth retardation, extra fingers and toes and, at times, other disorders dealing with sexual characteristics, the heart, and the kidneys. The syndrome is familial and appears to be associated with different genes that govern which factors of the syndrome affect individuals who have inherited it. The inheritance is recessive. Each parent is normal but has a normal gene and a mutated one. The child who has Bardet-Biedl inherits a mutated gene from each patient in most cases.

James Lupski, MD, PhD

However, Lewis, Lupski and Dr. Nicholas Katsanis, at Baylor at the time, found an unusual pattern of genetic inheritance that challenged the long-held notion about how diseases are inherited. In four families in which Bardet-Biedl syndrome had been found, those who showed signs of the disease indeed had inherited two mutated copies of a Bardet-Biedl gene. That was not enough, however, for them to show the signs or phenotype of the disease. A mutation in yet a third gene was required for that. In three cases, individuals had mutations of both copies of BBS2 and one mutation of BBS6. In a different family, the reverse was true. People in the families who inherited two mutated copies of a gene did not necessarily have the problems associated with the syndrome.

"We tend to think about regular recessive disease in terms of an on-off system," Katsanis said at the time. "If you inherit two mutated genes, you have the disease. If you have only one mutated copy, you do not have the problem at all. This has been the basis of Mendelian genetics and a key tool in discovering genes responsible for many genetic disorders."

"This may become a novel model for studying other complex human traits," said Lewis. In addition, understanding the genetics behind Bardet-Biedl could provide clues to more common disorders such as obesity, asthma, and diabetes as well as disorders that affect sight. All these are associated with this rare syndrome.

"Without the tools of molecular biology, this odd inheritance pattern would never have come to light," said Lupski, a professor of molecular and human genetics at Baylor. "While our findings do not disprove the theories of classical genetics, they do expand them."

More recently, Lewis and Katsanis have uncovered new information about how the disease occurs at the molecular level. “This study gives us a first powerful insight into how this disease comes about,” said Lewis.

“We discovered a new protein defective in Bardet-Biedl syndrome and, by studying its normal function in mammals and worms, we have been able to pin specific cellular structures as the sites of disease -- basal bodies of ciliated cells,” said Katsanis, now an assistant professor of ophthalmology at the McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine and a Baylor alumnus.

Upon discovering a new gene called BBS8, the researchers evaluated the function of the associated protein and found that it is always present in the base of cilia, hairlike structures that extend from the surface of specific cell types. They then looked in a worm model called Caenorhabditis elegans (C. elegans) and found that not only BBS8, but all other known BBS proteins function exclusively in cells that possessed cilia.

“We have a brand new and surprising culprit in familial obesity as well as other ailments,” said Katsanis. “This is a sharp departure from the way we have been thinking about problems such as body weight regulation, where most of the emphasis has been placed in the role of hormones and their interactions with cells. We now have a brand-new concept to explore, which is why we study these rare diseases: what they teach us is relevant to the biology of major health problems.”

“I want to understand why these kids are different and what they will tell us,” said Lewis. “How are their problems linked? There is something else about this we don’t understand yet.

“These kids have reactive airway diseases – 50 percent of them. A high percentage of them have recurrent otitis media (middle ear infection), but they are not immune deficient. They are obese and have renal disease. Some have their heart on the right side – their organs are reversed,” said Lewis.

“There is something about cilial development,” he said. Perhaps the cilia in the bronchial tree (of the lungs) do not work well, causing reactive airways disease. When the cilial cells don’t work to clean things out, there is problem with sinus drainage and the ear. Perhaps that has something to do with middle ear infections that plague these children.

Many of the children with Bardet-Biedl syndrome in the United States have speech problems that include difficulty saying their “p’s” and “b’s.” Others cannot blow bubbles with a soap ring. They are unable to spit out their toothpaste at night and cannot blow their noses when they have a cold.

“To me, the challenge now is that you have two gene interactions that cause disease. With two mutated genes, you don’t have disease. Add a third mutated gene and you have disease,” he said. The problems associated with Bardet-Biedl can vary from one child to another in a single family.

“This was a lesson in science,” said Katsanis, who did his postdoctoral work at Baylor. “It was a humbling lesson to me. You don’t really understand the answer you get until you ask the question in the right system. If you look at cells we typically use in the lab, you wouldn’t really come up with this idea. Most of the cells we used in the lab are not ciliated. That was not the correct system in which to ask.”

The work in C. elegans was critical to finding the answer, he said. “Once we got an idea of where to look and what questions to ask, a lot of things started falling into place beautifully. Now there are a lot of tantalizing hypothesizes,” he said. “This is a big springboard for more studies.”

(C. elegans is discussed in an earlier From the Laboratories issue: Nematode 'worms' its way into scientific history)
Science. 2001 Sep 21;293(5538):2256-9
Nature. 2003 Oct 9;425(6958):628-33

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