BAR HARBOR -- Researchers at The Jackson Laboratory have found a chromosomal region that interacts with the tub mutation to prevent normally occurring deafness in the tubby mouse model. Identification of the protective gene could help define shared molecular pathways underlying the multiple defects in tubby, including maturity-onset obesity, insulin resistance, and blindness.
The region, or locus, is known as moth1 (modifier of tubby hearing 1) and was traced to mouse Chromosome 2 by Drs. Akihiro Ikeda and Qing Yin Zheng in the laboratory of Drs. Patsy M. Nishina and Jürgen K. Naggert with colleagues from The Jackson Laboratory. The research appears as the cover article in the September 1999 issue of the journal Human Molecular Genetics.
The tubby mouse was characterized at the Laboratory in 1990 by Drs. Douglas Coleman and Eva Eicher as an autosomal recessive mutation in C57BL/6J ("B6") mice, one of a growing number of single-gene obesity models that includes ob (obese), db (diabetes), and cpefat. Tub was cloned in 1996 by the Nishina/Naggert group at The Jackson Laboratory and identified as a novel gene on chromosome 7.
Dr. Nishina and her colleagues have found that the tub mutation is a member of a novel family of genes that is widely distributed among species, from humans to maize. They have characterized TUB, the human homolog of tub, and family members called Tubby-Like Proteins: TULP1, TULP2, and TULP3. These mutated genes cause sensory defects in mice similar to retinitis pigmentosa and cone-rod dystrophy in humans.
Tubby mice develop hearing problems at three weeks of age, experiencing cochlear degeneration due to progressive loss of hair cells and neurons. Normal hearing results when sound waves cause the tiny hairs to oscillate, with the movement transmitted as electrical impulses through the hair cells to the brain. Hearing ability in mice is measured with a technique known as auditory brainstem response (ABR).
In their experiment, the Jackson Lab researchers crossbred C57BL/6J mice homozygous for the tub mutation with three other inbred mouse strains and used Quantitative Trait Loci (QTL) analysis to map genetic regions correlated with ABR thresholds in offspring. The results showed that all three strains carried an allele at the moth1 locus which acted to protect tub mice from hearing loss.
The researchers speculate that moth1 may be directly involved in the hearing impairment "cascade" induced by the tub mutation, which is known to induce cell death in sensory neurons. Because a single moth1 allele from the genetically unrelated strains is able to protect C57BL/6J-tub/tub mice against hearing loss, it is likely that B6 carries a recessive mutation at the moth1 locus which is necessary to mediate the effects of the tub mutation on hearing.
"Understanding 'natural' gene interactions that can delay or suppress hearing loss may provide a blueprint for creating therapeutics," says Dr. Nishina, a Staff Scientist at The Jackson Laboratory.
Moth1 maps to the region of mouse Chromosome 2 which is homologous to the region on human chromosome 15 containing a gene for Bardet-Biedl syndrome in humans. The obesity, insulin-resistance, and sensory deficits in tubby mice are similar to conditions observed in such rare genetic human diseases as Bardet-Biedl, Alström, and Prader-Willi syndromes. Further research could elucidate the common mechanisms thought to underlie these complex inherited diseases.
The research published in Human Molecular Genetics was supported by grants from the Foundation for Fighting Blindness and from AXYS Pharmaceuticals, Inc., as well as an institutional grant from the National Cancer Institute. Co-authors of the paper include Phillip Rosentiel, Terry Maddatu, Aamir Zuberi, Derry Roopenian, and Kenneth Johnson, all of The Jackson Laboratory, and Michael North of AXYS Pharmaceuticals.
Journal
Human Molecular Genetics