The “hyperspin” long-range enhancer deletion recapitulates disease phenotypes.
In recent years, improvements in genetic testing have made it much easier to discover the causes of rare genetic diseases, but sequence data can also present new puzzles. Take split hand/-foot malformation-1 syndrome (SHFM1), which causes limb deformities, such as joined fingers, and sometimes deafness. Candidate culprits were mutations in the genes DLX5 or DLX6, since defects in either gene cause SHFM1-like malformations in mice. But few people with SHFM1 carry the equivalent mutations.
In a recent mouse study, Johnson et al. found new clues to the mystery. The team examined deaf mice with a naturally occurring mutation they named hyperspin, which causes rapid circling behavior typical of mice with inner ear defects. They found that the hyperspin mice had inner ear malformations that recapitulate those seen in Dlx5-knockout mice—and the same features are sometimes part of the SHFM1 phenotype. The new mutation lies in the gene Slc25a13 and consists of a large deletion that spans introns as well as the exons that encode the majority of the SLC25A13 protein.
Despite the fact that hyperspin disrupts so much of the Slc25a13’s coding sequence, the researchers found that nonfunctional SLC25A13 protein wasn’t to blame for the mice’s phenotype. Completely knocking out Slc25a13 yielded mice with normal hearing and no indication of the hyperspin inner ear abnormalities. Instead, there were signs that a noncoding sequence in Slc25a13 regulates the expression of Dlx5, which is 660 kilobases away from the hyperspin deletion. Mouse embryos homozygous for the hyperspin mutation had strongly reduced expression of Dlx5 in the otic vesicle, which could have caused the inner ear defects they observed.
Unlike Dlx5-knockout mice, hyperspin mice can survive to adulthood, providing researchers a new model system for studying how a lack of Dlx5 affects inner ear function across the lifespan. This work also illustrates how pursuing unexpected occurrences, like this chance mutation in a lab mouse, can open new avenues of research.
Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice
Kenneth R. Johnson, Leona H. Gagnon, Cong Tian, Chantal M. Longo-Guess, Benjamin E. Low, Michael V. Wiles, Amy E. Kiernan
Genetics 2018 208: 1165-1179; https://doi.org/10.1534/genetics.117.300447