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

被引：0

作者：

Baril, Stefanie A. ^{[1
]}

Wilson, Katie A. ^{[2
,3
]}

Shaik, Md Munan ^{[4
]}

Fukuda, Yu ^{[1
]}

Umans, Robyn A. ^{[5
]}

Barbieri, Alessandro ^{[6
,7
]}

Lynch, John ^{[1
]}

Gose, Tomoka ^{[1
]}

Myasnikov, Alexander ^{[4
]}

Oldham, Michael L. ^{[4
]}

Wang, Yao ^{[1
]}

Zhu, Jingwen ^{[1
,8
]}

Fang, Jie ^{[9
,10
]}

Zuo, Jian ^{[9
]}

Kalathur, Ravi C. ^{[4
]}

Ford, Robert C. ^{[6
]}

Coffin, Allison ^{[11
]}

Taylor, Michael R. ^{[5
,12
]}

O'Mara, Megan L. ^{[2
,13
]}

Schuetz, John D. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[2] Australian Natl Univ, Coll Sci, Res Sch Chem, Canberra, ACT, Australia

[3] Mem Univ Newfoundland, Dept Biochem, St John, NF, Canada

[4] St Jude Childrens Res Hosp, Dept Struct Biol, Memphis, TN USA

[5] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN USA

[6] Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Manchester, England

[7] ASTAR, Bioinformat Inst BII, Singapore, Singapore

[8] Univ Tennessee, Hlth Sci Ctr, Dept Pharmaceut Sci, Memphis, TN 38103 USA

[9] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN USA

[10] St Jude Childrens Res Hosp, Dept Surg, Memphis, TN USA

[11] Washington State Univ Vancouver, Dept Integrat Physiol & Neurosci, Vancouver, WA USA

[12] Univ Wisconsin Madison, Sch Pharm, Pharmaceut Sci Div, Madison, WI USA

[13] Univ Queensland, Australian Inst Bioengn & Nanotechnol, St Lucia, Qld, Australia

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

美国国家卫生研究院; 澳大利亚研究理事会;

关键词：

LATERAL-LINE SYSTEM; MISSENSE MUTATIONS; LIPID-COMPOSITION; CYSTIC-FIBROSIS; HAIR-CELLS; ABCB6; ZEBRAFISH; HEARING; TRANSPORTER; MEMBRANE;

D O I：

10.1038/s41467-024-53663-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 & Aring;) 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. ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition that can present with hearing loss. Here, the authors use zebrafish and mice to perform experiments suggesting that ABCB6 plays a role in inner ear development.

引用

页数：17

共 90 条

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