09/22/1999 07:00:00

Gene linked to human kidney disease is also responsible for mating in roundworms

PASADENA-For a male nematode, the LOV-1 gene couldn't be more aptly named. The millimeter-long roundworm, if its LOV-1 gene is functioning properly, has the eagerness to mate and the instincts to perform successfully.

But if the LOV-1 gene is disabled, the male nematode is truly clueless. The fact that "LOV" is an acronym for "location of vulva" pretty much says it all.

While there is no such single gene controlling sexual interest and instinct in humans, California Institute of Technology researchers who recently identified the LOV-1 gene say there is a similar human gene involved in a type of kidney disease.

In the Sept. 23 issue of the British journal Nature, Caltech researchers Paul Sternberg and Maureen Barr write of their discovery that the LOV-1 gene has a sensory role in nematodes. The human homolog (or counterpart) is PKD1, or polycystic kidney disease gene 1.

In other words, a male nematode that has this particular gene intact is able and willing to mate, while a human with the gene intact is disease-free. But if the genes are respectively knocked out, the nematode is sexually dysfunctional and the human is prone to autosomal dominant polycystic kidney disease, a serious disease that afflicts about one in 1,000 people and may ultimately result in renal failure.

"This is a surprise," says Sternberg, a biology professor at Caltech. "We can only speculate on what the connection might be."

PKD1 and a second gene, PKD2, account for about 95 percent of all cases of autosomal dominant polycystic kidney disease. These genes cause the human body to produce polycystin 1 and polycystin 2, which are thought to work somehow in concert at the molecular level.

In an analogous manner, the LOV-1 gene also seems to work in concert with the PKD-2 gene, which in nematodes is the counterpart of the PKD2 gene in humans. The fact that the genes in both humans and nematodes seem to work in pairs actually strengthens the likelihood that there is some underlying molecular relationship, Sternberg says.

Much of the lab work leading to this discovery was done by Maureen Barr, a postdoctoral scholar in Sternberg's lab who painstakingly watched in a microscope for male nematodes who were not successfully mating.

Barr then singled out the dysfunctional males and used standard genetic screening techniques and DNA sequencing analysis to identify the LOV-1 gene, which when mutated, is responsible for the lack of mating behavior.

While the researchers are not clear on why a gene involved in mating behavior in one species would be involved in disease in another, they say there could be a couple of possible explanations.

For one thing, the connection between the human gene and the worm gene might be very basic. Perhaps the gene is involved in setting up polarity of human kidney cells and polarity of worm neurons that govern sexual behavior.

In the case of the worm, the LOV-1 might actually act as part of a sensory signaling pathway responding to the presence of a mating partner by altering the electrical properties of the specific nerve cell that senses the mate.

Or perhaps the underlying relationship has to do with cell structure, Sternberg says. In this case, the LOV-1 protein might function as a molecular scaffold for other molecules, or promote the assembly of many molecules to create structures such as the sensory neuronal cilia.

Sternberg and Barr say the scientific goal of the study was to investigate ways in which genes influence behavior. But the findings could also serendipitously point to new avenues for research on autosomal dominant polycystic kidney disease.

"This is a mystery disease, so it could be that renal failure is just the first defect in a disease with broader manifestations," Sternberg says. In that case, improved knowledge at the molecular level could lead to different approaches in identifying treatments or even a cure.

"Here's a new way to study the basic mechanism," Sternberg says.

Written by Robert Tindol