The role of ATP-binding Cassette subfamily B member 6 in the inner ear

Stefanie A. Baril, Katie A. Wilson, Md Munan Shaik, Yu Fukuda, Robyn A. Umans, Alessandro Barbieri, John Lynch, Tomoka Gose, Alexander Myasnikov, Michael L. Oldham, Yao Wang, Jingwen Zhu, Jie Fang, Jian Zuo, Ravi C. Kalathur, Robert C. Ford, Allison Coffin, Michael R. Taylor, Megan L. O’Mara and John D. Schuetz ()
Additional contact information
Stefanie A. Baril: St. Jude Children’s Research Hospital
Katie A. Wilson: The Australian National University
Md Munan Shaik: St. Jude Children’s Research Hospital
Yu Fukuda: St. Jude Children’s Research Hospital
Robyn A. Umans: St. Jude Children’s Research Hospital
Alessandro Barbieri: The University of Manchester
John Lynch: St. Jude Children’s Research Hospital
Tomoka Gose: St. Jude Children’s Research Hospital
Alexander Myasnikov: St. Jude Children’s Research Hospital
Michael L. Oldham: St. Jude Children’s Research Hospital
Yao Wang: St. Jude Children’s Research Hospital
Jingwen Zhu: St. Jude Children’s Research Hospital
Jie Fang: St. Jude Children’s Research Hospital
Jian Zuo: St. Jude Children’s Research Hospital
Ravi C. Kalathur: St. Jude Children’s Research Hospital
Robert C. Ford: The University of Manchester
Allison Coffin: Washington State University Vancouver
Michael R. Taylor: St. Jude Children’s Research Hospital
Megan L. O’Mara: The Australian National University
John D. Schuetz: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.

Date: 2024
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DOI: 10.1038/s41467-024-53663-x

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