Gene believed linked to serious kidney disease

December 10, 2000

New Haven, Conn. - Defects in the thin, hair-like projections lining the ducts and tubules of the kidneys, and known as primary cilia, may be responsible for a kidney disease affecting one in 10,000 children, a Yale researcher and collaborators have found.

Autosomal recessive polycystic kidney disease (ARPKD) also is thought to be responsible for an even higher proportion of stillbirths and prenatal deaths. In fact, mice with ARPKD die before or shortly after birth.

And since cilia exists in almost all cells in the body, a shortage or absence of the cilia may be tied to many other diseases, said Joel Rosenbaum, professor in the Department of Molecular, Cellular and Developmental Biology.

"For example, the outer segment of rods and cones of our retina containing the visual pigments and responsible for vision are derived from primary cilia," Rosenbaum said in reporting his findings at the Dec. 9-13 annual international meeting of the American Society for Cell Biology in San Francisco. "We expect that problems with genes like the one that results in ARPKD will also have effects on the cilia of other tissues, such as the retina, and result in retinal degeneration and blindness."

Rosenbaum said it is already known that mice with defects in primary cilia, and which have ARPKD, also have situs inversus, in which organs such as the heart may be positioned on the right side of the body rather than on the left, which is the normal side.

The cilia in question are not the ones most persons are familiar with, such as the hair-like projections in lungs that trap pollutants and dust or those that form the tails of sperm cells and power their movement. Primary cilia lack many of the internal structures that permit them to move.

Each of many of the kidney cells contain a single long cilium, whose function is unknown. While studying a genetic "knock out" mouse, which is one in which a gene has been mutated, Rosenbaum and his colleagues discovered that the mouse with its mutated Tg737 gene had all of the major characteristics of ARPKD.

"The gene which had been 'knocked out' in this mouse was the same gene which when knocked out in a well-studied green alga resulted in an algal cell with no flagella," Rosenbaum said. A normal, single-celled alga swims by thrashing its cilia, but the researchers discovered the algae with mutations in the Tg737 gene never form cilia.

When Rosenbaum and his collaborators used electron microscopy to study the kidneys of the Tg737 knock out mouse they found the kidney cells had fewer and shorter primary cilia. They concluded that the gene they were studying is essential for the formation of cilia and flagella, and in the case of the knock out mouse, the gene is linked to ARPKD.

"We found the gene in the alga first, cloned it and sequenced it, and found it was the same as the gene others had studied in the mice with polycystic kidney disease. But they didn't know why the mice had ARPKD. We related it to the celia," Rosenbaum said. "We showed that the reason the mouse probably had the kidney disease was because the cilia were not being formed correctly in the kidney. The question now is just how does the lack of primary cilia in the kidney result in the disease. We think the cilia are filling a sensory function in the kidney."
Other members of the research team included Gregory Pazour and George Witman of the University of Massachusetts Medical School and Douglas Cole of the University of Idaho. Witman received his Ph.D. in 1970 in Rosenbaum's laboratory at Yale. Cole was a post-doctoral fellow until recently in Rosenbaum's lab, and Pazour was a post doctoral fellow with Witman.

Yale University

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