First author Stefanie Baril, PhD, and corresponding author John Schuetz, PhD, St. Jude Department of Pharmacy and Pharmaceutical Sciences, tracked a peculiar hearing deficiency observed in cases of a rare skin disorder to the ABC transporter protein family.
Dyschromatosis universalis hereditaria (DUH) is a rare skin pigmentation disorder linked to the protein ABCB6. Relatively little is understood about the long list of other DUH symptoms, which range from learning difficulties to insulin-dependent diabetes, and their potential link to ABCB6. Scientists at St. Jude Children’s Research Hospital used a complementary biochemical and biophysical approach to study ABCB6 mutations identified in DUH patients. With further analysis of ABCB6 in two model organisms, scientists found an unexpected link between ABCB6 and hearing deficits, which have been observed in DUH patients, implying that certain cases of hearing deficits may be directly attributable to defects in the protein. The findings were published today in Nature Communications.
The ABC family of proteins is responsible for transmembrane transport, serving primarily as toxin removal specialists in cells. One member of this large, multifunctional family, ABCB6, specializes in heavy metal transport but is also tied to the biosynthesis of heme, the iron-containing component of hemoglobin. Unsurprisingly, ABCB6 disruption has been linked to numerous blood disorders. However, ties to other ailments have been unclear.
“DUH is most known for a pigmentation defect, but we knocked out the gene for ABCB6 in mice and saw no evidence of defects in pigmentation,” explained John Schuetz, PhD, St. Jude Department of Pharmacy and Pharmaceutical Sciences. “We concluded there must be something else. We looked at all the potential phenotypes in DUH, and one of the other ones that was referenced frequently was hearing defects.” Since DUH is an orphan disease affecting a few thousand people a year, there is no official tally of DUH patients that co-present with hearing deficits.
ABCB6 mutation links pigmentation defect with hearing impairment
Schuetz’s team demonstrated an unexpected link between inner ear development and the ABCB6 transporter protein.
By closely examining the inner ear of zebrafish and mice that had mutated ABCB6 transporters, the multi-institutional researchers team concluded that there were clear signs of hearing deficit in both organisms. In zebrafish, the knockout caused reduced inner ear and lateral line hair cell numbers, which detect acoustic and vibrational stimuli, as well as a reduction of otoliths or “ear stones” in the inner ear, which affect balance. The impact of this was immediately apparent.
“Instead of orienting horizontally, many of the zebrafish were orientated straight up. And it was persistent,” explained Schuetz. In mice, reduced hearing sensitivity was the telltale sign of a hearing deficit.
To complement these studies, the researchers obtained a high-resolution structure of the ABCB6 protein using cryo-electron microscopy and performed molecular dynamics simulations using a model of a DUH-mutant ABCB6, which lacks functional capabilities. ABCB6 transporters function in pairs called dimers; however, the researchers found that this mutant disrupted the protein’s ability to form a functioning dimer.
“The simulations showed that the mutation elongates a loop in the structure, preventing ATP, the energy currency of the cell, from binding to the protein,” explained first author Stefanie Baril, PhD, Department of Pharmacy and Pharmaceutical Sciences. “Both halves of an ABCB6 dimer must bind and use energy from ATP to move compounds across the cell. So, a dimer containing one mutant and one normal copy is essentially nonfunctional.”
The findings have opened many opportunities to probe ABCB6 and its connection with DUH. Considering ABCB6 knockout mice presented with hearing deficits but not skin pigmentation issues, the protein may be more intrinsically tied to hearing than initially understood.
“There may be individuals who have defects in hearing that might be attributable to ABCB6 defects,” Schuetz said. “This could indicate that people with ABCB6 defects are more susceptible to hearing impairment or other symptoms associated with DUH.”
Authors and funding
The study’s other authors are Katie Wilson, Australian National University and Memorial University of Newfoundland; Alessandro Barbieri, The University of Manchester and Bioinformatics Institute, Agency for Science, Technology and Research, Singapore; Robert Ford, The University of Manchester; Allison Coffin, Washington State University Vancouver; Megan O’Mara, The Australian National University and The University of Queensland; Michael Taylor, St. Jude and University of Wisconsin-Madison; Munan Shaik, Yu Fukuda, Robyn Umans, John Lynch, Tomoka Gose, Alexander Myasnikov, Michael Oldham, Yao Wang, Jingwen Zhu, Jie Fang, Jian Zuo, and Ravi Kalathur, St. Jude.
The study was supported by grants from the National Institutes of Health (RO1NS116043, R01CA194057, R01CA194206, P30 CA21745 and P30 CA021765), the National Institute on Deafness and Other Communication Disorders (R15DC013900-01 and R01DC020701-01A1), the Australian Research Council (DP200100535), and ALSAC, the fundraising and awareness organization of St. Jude.
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