A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse

Grimm, Christian, Cuajungco, Math P, Van Aken, Alexander F J, Schnee, Michael, Jörs, Simone, Kros, Corné J, Ricci, Anthony J and Heller, Stefan (2007) A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proceedings of the National Academy of Sciences, 104 (49). pp. 19583-19588. ISSN 0027-8424

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Abstract

Homozygote varitint-waddler (Va) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular and pigmentation deficiencies, sterility, and perinatal lethality. Here we show that the varitint-waddler isoform of TRPML3 carrying an A419P mutation represents a constitutively active cation channel that can also be identified in native varitint-waddler hair cells as a distinct inwardly rectifying current. We hypothesize that the constitutive activation of TRPML3 occurs as a result of a helix-breaking proline substitution in transmembrane-spanning domain 5 (TM5). A proline substitution scan demonstrated that the inner third of TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions in TM5 of other TRP channels revealed that TRPML1, TRPML2, TRPV5, and TRPV6 display a similar susceptibility at comparable positions, whereas other TRP channels were not affected. We conclude that the molecular basis for deafness in the varitint-waddler mouse is the result of hair cell death caused by constitutive TRPML3 activity. To our knowledge, our study provides the first direct mechanistic link of a mutation in a TRP ion channel with mammalian hearing loss.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Depositing User: Alexander VanAken
Date Deposited: 06 Feb 2012 19:50
Last Modified: 21 May 2012 15:46
URI: http://sro.sussex.ac.uk/id/eprint/22437
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