Mus musculus, the common mouse, comes in a variety of uncommon coat colors, body shapes and mutant strains. One mutant sports the handle "varitint-waddler."

"The most obvious defect in these mice," observed molecular biologist Konrad Noben-Trauth, "is its variegated coat color. A normal mouse looks kind of brown or agouti. In this varitint-waddler strain, the mice wear whitish patches randomly distributed on the surface of the body. It's a marker of the mutant strain, though not unique to it. There are other mutants causing similar phenotypes.

"Varitint-waddler's behavior is different," Noben-Trauth continued. "What we see in this strain of mutants is hyperactivity and erratic circling. As in a test system, these varitint-waddlers make up to 800 circles - rotations - per hour. The hourly distance they travel on average is 500 to 600 meters. Their cage has a surface of 30 by 25 centimeters. And they pretty much use the surface of that cage to run around in circles.

"If we use the term behavior,'" he went on, "it sort of reflects that there might be a phenotypic pattern in their central nervous system or brain. But they have other systems that control this behavior in the peripheral nervous system. In this particular varitint-waddler mutant, the defect is in the inner ear, which contains the organ of balance. So the chochlea, which is the auditory system, and the vestibular organ are anatomically very close together. They share the same compartment, so to speak. And also the sensory cells that help mice - and us - to hear, and balance ourselves. Both mammalian species, murine and human, are structurally and functionally very similar. Basically, if you have a defect in the auditory hair cell you very likely have a defect in the vestibular hair cell, too. So mechanically it's pretty much the same. A family of Mucolipin genes (Mcoln for short) are found in the genomes of mice, fruit flies, nematodes and mammals - including people."

The Proceedings of the National Academy of Sciences (PNAS), released online Oct. 22, 2002, carries a paper titled: "Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice." Its senior author is Noben-Trauth, at the NIH's Institute on Deafness and Other Communication Disorders in Rockville, Md.

Stereocilia Bend Over Backwards

"Our first finding," he told BioWorld Today, "is that we have identified a gene that causes deafness in mice. That is the basic message. The second aspect is that the gene, which is involved in melanocytes [pigment cells], also causes pigmentation in that mouse's coat-color defect.

"The Mucolipin gene we have identified is in itself novel," Noben-Trauth continued. "Also, the function associated with it appears to be new among the deafness genes. The Mcoln gene is predicted to function as an ion channel. This is very exciting, for two reasons: One is we did find that this gene localizes to a region on cells that are involved in signaling transduction. It is a mechano-sensitive pathway. On top of its stereocilia - hair cells - there is a layer, a membrane, against which the cells are pushing. Therefore, the stereocilia bend over with a mechanical force that we believe opens transduction channels. So our data indicate that our candidate gene might be involved in this initial step in the mechano-sensitive receptor or channel.

"A Mucolipin1 gene was identified three years ago," Noben-Trauth recalled, "and the mutations in the human version involve a neurodegenerative disease. The genome of this gene family has been sequenced in Drosophila, and also the homologue or cousin of that gene in C. elegans. But in those two species there's only one copy of that gene in the genome. In mammals, such as mice and humans, there are three copies. So now our work identifies those two additional copies, Mcoln3 and Mcoln2, on human chromosome 1 [Mcoln1 is on chromosome 19].

"The human mutant version causes some sort of mental retardation and variable degrees of growth and psychotic neuropathy. The cellular defect is that mutations in that gene cause dysfunction in vesicles - intracellular droplets where certain substances are being stored and transported toward vesicles in the cytoplasm. So with dysfunctions in those vesicles, and in patients having the disease, those vesicles enlarge and form very large vacuoles in the cells, which certainly leads to cell degeneration. Our second finding," Noben-Trauth went on, "is that Mcoln3 seems to be involved in that process in mice, and also in humans. We find the protein localized in cytoplasmic compartments, which are very likely to be vesicles as well."

Diagnostics? No Problem; Therapeutics? Count Genes!

"As for the melanocyte connection," Noben-Trauth recounted, "look at the cochlea. It's the hearing organ, and there are a number of important structures. One is the organ of Corti, which contains the hair cells. The second is the stria vascularis of the cochlear duct. It is located nearby, and contains different cell types. Their function is to secrete certain ions - mainly potassium - into a certain space, and create an endocochlear potential. If you have a defect in those melanocytes, then they do not secrete potassium, which powers the endocochlear potential. And without that potential, there is simply no hearing. That's one of the unique features of the varitint-waddler strain," Noben-Trauth pointed out, "which acts in both hair cells and melanocytes.

"Our primary focus now is finding or defining the function of Mucolipin. We will do two things: first, tissue-culture experiments, with electrophysiological recording, and second, look directly at mutant mice, which we have already done, to see if we see a different mechano-transduction. It might have some implications for future diagnostic or therapeutic endpoints, which are far ahead of us.

"Diagnostics is not a problem," he suggested. "It may just be a matter of the test system and how fast they are implemented. But an entry point for therapy is that we need to identify all those many different genes. The bad news is there are so many different genes [and] you would have to define a strategy for each of them. So we're talking about easily 50 to 60 genes," he concluded, "that cause deafness worldwide."