Can a fish with a malformed jaw tell us something about hearing loss in mice and humans? The answer is yes, according to a new publication in Scientific Reports.
In a twist of evolution, the structures supporting the jaws of ancestral fish gave rise to three tiny bones in the mammalian middle ear: the malleus, incus and the stapes, which transmit sound vibrations. Therefore, if a genetic change causes a jaw malformation in a fish, an equivalent genetic change could trigger hearing defects in mice and humans.
To test this, first author and PhD student Camilla Teng from the USC Stem Cell laboratory of Gage Crump, PhD, associate professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC, and her colleagues studied two genes — JAG1 and NOTCH2 — that are mutated in most patients with Alagille syndrome (AGS). In nearly half of patients, AGS involves hearing loss — in addition to liver, eye, heart and skeletal defects. While some of the hearing loss is sensorineural, resulting from deficits in the sensory cells of the inner ear, the researchers also wondered about the contribution of conductive hearing loss, involving structural components of the middle ear such as the vibrating bones.
Knowing that the equivalent genetic mutations caused jaw malformations in zebrafish, the researchers introduced the mutations into mice and observed defects in both the incus and stapes bones, and corresponding hearing loss.
They then attended Alagille Alliance meetings in 2011 and 2014 and performed tests to determine if patients’ hearing loss was conductive, sensorineural or mixed. As their findings in zebrafish and mice predicted, conductive hearing loss was the most common type — affecting nearly one-third of ears.
CT scans of AGS patients revealed a more complicated picture: a surprising diversity of structural defects in the middle ear with variable effects on hearing.
“Our study highlights a mostly overlooked phenotype of Alagille syndrome,” Teng said. “If patients are aware of possible conductive hearing loss earlier in life, then they can more promptly seek medical aids for an improved quality of life.”
Co-authors include: Hai-Yun Yen, PhD, Lindsey Barske, PhD, postdoctoral scholar — research associate, Juan Llamas, research lab specialist, and John Go, MD, assistant professor of clinical radiology from the Keck School; and Bea Smith, AUD, and Pedro A. Sanchez-Lara, MD, assistant professor of clinical pathology and pediatrics at the Keck School, from Children’s Hospital Los Angeles.
Fifty percent of this project was supported by $400,000 of federal funding from the National Institutes of Health (grants/fellowship DE018405, DE024031, DE016320 and DC009975), and the other 50 percent by $400,000 of private funding from the March of Dimes. Barske received a fellowship from the A.P. Giannini Foundation.
— Cristy Lytal