Di Palma, F. et al. Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc. Natl. Acad. Sci. USA 99, 14994-14999

Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2002; 99(23):14994-9. DOI: 10.1073/pnas.222425399
Source: PubMed


Deafness in spontaneously occurring mouse mutants is often associated with defects in cochlea sensory hair cells, opening an avenue to systematically identify genes critical for hair cell structure and function. The classical semidominant mouse mutant varitint-waddler (Va) exhibits early-onset hearing loss, vestibular defects, pigmentation abnormalities, and perinatal lethality. A second allele, Va(J), which arose in a cross segregating for Va, shows a less severe phenotype. By using a positional cloning strategy, we identify two additional members of the mucolipin gene family (Mcoln2 and Mcoln3) in the 350-kb Va(J) minimal interval and provide evidence for Mcoln3 as the gene mutated in varitint-waddler. Mcoln3 encodes a putative six-transmembrane-domain protein with sequence and motif similarities to the family of nonselective transient-receptor-potential (TRP) ion channels. In the Va allele an Ala419Pro substitution occurs in the fifth transmembrane domain of Mcoln3, and in Va(J), a second sequence alteration (Ile362Thr) occurring in cis partially rescues the Va allele. Mcoln3 localizes to cytoplasmic compartments of hair cells and plasma membrane of stereocilia. Hair cell defects are apparent by embryonic day 17.5, assigning Mcoln3 an essential role during early hair cell maturation. Our data suggest that Mcoln3 is involved in ion homeostasis and acts cell-autonomously. Hence, we identify a molecular link between hair cell physiology and melanocyte function. Last, MCOLN2 and MCOLN3 are candidate genes for hereditary and/or sporadic forms of neurosensory disorders in humans.

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    • "Mutations in the human TRPML1 gene cause Mucolipidosis Type IV, a lysosomal storage disorder [5], [6]. A point mutation in the murine Trpml3 gene causes the varitint-waddler (Va) phenotype manifested in pigmentation defects, circling behavior, and hearing loss [7]. The Va mutation causes a constitutively open channel, resulting in elevated [Ca2+]i, which ultimately leads to apoptotic death of cells expressing TRPML3 [1], [8]–[10]. "
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    ABSTRACT: TRPML3 and TRPV5 are members of the mucolipin (TRPML) and TRPV subfamilies of transient receptor potential (TRP) cation channels. Based on sequence similarities of the pore forming regions and on structure-function evidence, we hypothesized that the pore forming domains of TRPML and TRPV5/TRPV6 channels have similarities that indicate possible functional interactions between these TRP channel subfamilies. Here we show that TRPML3 and TRPV5 associate to form a novel heteromeric ion channel. This novel conductance is detectable under conditions that do not activate either TRPML3 or TRPV5. It has pharmacological similarity with TRPML3 and requires functional TRPML3 as well as functional TRPV5. Single channel analyses revealed that TRPML3 and TRPV5 heteromers have different features than the respective homomers, and furthermore, that they occur in potentially distinct stoichiometric configurations. Based on overlapping expression of TRPML3 and TRPV5 in the kidney and the inner ear, we propose that TRPML3 and TRPV5 heteromers could have a biological function in these organs.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "TRPML3 expression has been detected in inner ear sensory hair cells [4], [17], and the Va mutation of the channel leads to hair cell degeneration and deafness [4], [5]. On the other hand, hair cell death-mediated deafness (due to a constitutive active ion channel) is not sufficient to justify a function in the hearing process itself. "
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    ABSTRACT: TRPML3, a member of the transient receptor potential (TRP) family, is an inwardly rectifying, non-selective Ca2+-permeable cation channel that is regulated by extracytosolic Na+ and H+ and can be activated by a variety of small molecules. The severe auditory and vestibular phenotype of the TRPML3(A419P) varitint-waddler mutation made this protein particularly interesting for inner ear biology. To elucidate the physiological role of murine TRPML3, we conditionally inactivated Trpml3 in mice. Surprisingly, lack of functional TRPML3 did not lead to circling behavior, balance impairment or hearing loss.
    Full-text · Article · Dec 2010 · PLoS ONE
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    • "The current is inhibited by an acid extracytosolic (analogous to the luminal side) pH (Kim et al. 2008). Notably, elimination of TRPML3 regulation by extracytosolic pH has the same functional and cellular phenotype as the A419P (Va) mutation, a gain-of-function mutation that causes the varitint-waddler phenotype (a disease characterized by deafness, circling behavior, and pigmentation defects) (Di Palma et al. 2002). This mutation is likely to disrupt channel-gating by locking the channel in an open state, making the channel constitutively active and yielding much larger currents (Cuajungco and Samie 2008); although basic properties, such as I-V characteristics, single channel conductance, and ion selectivity have not changed (Kim et al. 2007; Nagata et al. 2008). "
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    ABSTRACT: The 28 mammalian members of the super-family of transient receptor potential (TRP) channels are cation channels, mostly permeable to both monovalent and divalent cations, and can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are widely expressed in a large number of different tissues and cell types, and their biological roles appear to be equally diverse. In general, considered as polymodal cell sensors, they play a much more diverse role than anticipated. Functionally, TRP channels, when activated, cause cell depolarization, which may trigger a plethora of voltage-dependent ion channels. Upon stimulation, Ca2+ permeable TRP channels generate changes in the intracellular Ca2+ concentration, [Ca2+]i, by Ca2+ entry via the plasma membrane. However, more and more evidence is arising that TRP channels are also located in intracellular organelles and serve as intracellular Ca2+ release channels. This review focuses on three major tasks of TRP channels: (1) the function of TRP channels as Ca2+ entry channels; (2) the electrogenic actions of TRPs; and (3) TRPs as Ca2+ release channels in intracellular organelles.
    Full-text · Article · Oct 2010 · Cold Spring Harbor perspectives in biology
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