Genetic Analyses of the Mouse Deafness Mutations Varitint-Waddler (Va) and Jerker (Espnje)

Kim, Hung J.; Jackson, T.; Noben-Trauth, Konrad

doi:10.1007/s10162-002-3011-0

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…6B), measurements that are in agreement with those in a previous report (15). The results for Mcoln3 ϩ/ϩ ; Atp2b2 dfw/ϩ mice are in accordance with previous findings of no significant differences in comparison with wild-type controls (16).…”

Section: Abr Thresholds For Mcoln3supporting

confidence: 83%

Life and Death of Sensory Hair Cells Expressing Constitutively Active TRPML3

Jörs¹,

Heller

2009

Journal of Biological Chemistry

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The varitint-waddler mutation A419P renders TRPML3 constitutively active, resulting in cationic overload, particularly in sustained influx of Ca 2؉ . TRPML3 is expressed by inner ear sensory hair cells, and we were intrigued by the fact that hair cells are able to cope with expressing the TRPML3(A419P) isoform for weeks before they ultimately die. We hypothesized that the survival of varitint-waddler hair cells is linked to their ability to deal with Ca 2؉ loads due to the abundance of plasma membrane calcium ATPases (PMCAs). Here, we show that PMCA2 significantly reduced [Ca 2؉ ] i increase and apoptosis in HEK293 cells expressing TRPML3(A419P). The deaf-waddler isoform of PMCA2, operating at 30% efficacy, showed a significantly decreased ability to rescue the Ca 2؉ loading of cells expressing TRPML3(A419P). When we combined mice heterozygous for the varitint-waddler mutant allele with mice heterozygous for the deaf-waddler mutant allele, we found severe hair bundle defects as well as increased hair cell loss compared with mice heterozygous for each mutant allele alone. Furthermore, 3-week-old double mutant mice lacked auditory brainstem responses, which were present in their respective littermates containing single mutant alleles. Likewise, heterozygous double mutant mice exhibited severe circling behavior, which was not observed in mice heterozygous for TRPML3(A419P) or PMCA2(G283S) alone. Our results provide a molecular rationale for the delayed hair cell loss in varitint-waddler mice. They also show that hair cells are able to survive for weeks with sustained Ca 2؉ loading, which implies that Ca 2؉ loading is an unlikely primary cause of hair cell death in ototoxic stress situations.Varitint-waddler (Va) mice express a mutant isoform (A419P) of the transient receptor potential channel TRPML3 (murine gene symbol, Mcoln3) that results in profound hearing loss, vestibular defects (circling behavior, imbalance, head bobbing, waddling), pigmentation deficiencies, sterility, and perinatal lethality in homozygous animals (1). A second Mcoln3 variant (Va J ) that arose in the Va background carries two mutations (I362T and A419P) and shows a phenotype with reduced severity, particularly in heterozygous animals (1). The A419P mutation in Va and Va J mice is located in transmembranespanning domain 5(TM5) 3 of TRPML3, where it leads to a constitutively open channel, resulting in highly elevated [Ca 2ϩ ] i (2-5). In contrast to the effect of the A419P mutation on TRPML3 channel activity, the single I362T mutation does not appear to affect [Ca 2ϩ ] i (3,5). When combined with the A419P mutation, as found in Va J mice, the constitutive activity of this mutant TRPML3 isoform is comparable with that of A419P alone (2-5).Here, we show that HEK293 cells expressing TRPML3-(A419P) or TRPML3(I362T/A419P) undergo rapid apoptosis. This apoptosis is suppressed by coexpression of plasma membrane calcium ATPase type 2 (PMCA2). In varitint-waddler mice, sensory hair cells survive for weeks after birth (6), which raised the quest...

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Section: Abr Thresholds For Mcoln3supporting

confidence: 83%

Life and Death of Sensory Hair Cells Expressing Constitutively Active TRPML3

Jörs¹,

Heller

2009

Journal of Biological Chemistry

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“…Concordance between the espin gene and the jerker mutation has been confirmed by detailed physical mapping studies [37,38].…”

Section: Jerker Deafness Mutation In the Mouse Espin Genementioning

confidence: 77%

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Sekerková

Zheng

Loomis

et al. 2006

Cell. Mol. Life Sci.

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The espins are novel actin-bundling proteins that are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle of hair cell stereocilia and are the target of deafness mutations in mice and humans. Espins are also enriched in the microvilli of taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells, suggesting that espins play important roles in the microvillar projections of vertebrate sensory cells. Espins are potent actin-bundling proteins that are not inhibited by Ca 2+ . In cells, they efficiently elongate parallel actin bundles and, thereby, help determine the steady-state length of microvilli and stereocilia. Espins bind actin monomer via their WH2 domain and can assemble actin bundles in cells. Certain espin isoforms can also bind phosphatidylinositol 4,5-bisphosphate, profilins or SH3 proteins. These biological activities distinguish espins from other actin-bundling proteins and may make them well-suited to sensory cells. KeywordsEspin; actin; hair cell; stereocilia; microvilli; sensory; deafness; taste The stereocilia and microvilli of vertebrate sensory cells and their actinbundling proteinsMany classes of vertebrate sensory cells detect chemical or mechanical stimuli through microvilli or their derivatives, such as stereocilia. These relatively long-lived, fingerlike specializations of the plasma membrane are built around a common cytoskeletal element -the parallel actin bundle (PAB) [1]. PABs consist of tightly packed collections of actin filaments cross-linked by actin-bundling proteins. The filaments are aligned along their longitudinal axis and display a uniform polarity with respect to their preferred ends for actin monomer addition, which in microvilli and stereocilia is positioned at the distal tip. The PAB displays hallmarks of a supramolecular scaffold that determines the placement, dimensions, flexibility and signaling properties of microvilli and stereocilia. Although filopodia also contain a PAB at their core and are believed to sense the local environment, they are considerably more dynamic and differ significantly from microvilli and stereocilia in their molecular composition and biogenesis [2].

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“…Nonetheless, it has been reported that the Va/+ heterozygotes suffer from hearing loss, vestibular dysfunction (circling behavior, head-bobbing, waddling), and coat color dilution. Meanwhile, the Va J /Va J homozygote mice are also deaf with almost similar coat color dilution as the Va/+ heterozygotes, but for an unknown reason, the Va J /Va J homozygotes appear to have no vestibular defects [4,7,11,17]. Furthermore, the Va J /+ heterozygote mice show a much milder phenotype-exhibiting normal vestibular function, partial hearing, and a very small amount of pigmentation deficiency [4,11].…”

Section: The Varitint-waddler (Va) Phenotypesmentioning

confidence: 91%

“…This is perhaps due to the observed lethality of the homozygous alleles and sterility of progenies that do survive (cited in ref. [4,7,11,17]). Nonetheless, it has been reported that the Va/+ heterozygotes suffer from hearing loss, vestibular dysfunction (circling behavior, head-bobbing, waddling), and coat color dilution.…”

Section: The Varitint-waddler (Va) Phenotypesmentioning

confidence: 97%

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The varitint–waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence

Cuajungco

Samie

2008

Pflugers Arch - Eur J Physiol

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The transient receptor potential mucolipins (TRPMLs) are the most recently discovered subfamily of TRP ion channel proteins. Positional cloning approach has identified two mutations in the TRPML3 (Mcoln3) gene that cause the varitint-waddler mouse phenotypes. Short for variable tint (diluted coat color), the varitint-waddler consists two phenotypes Va and Va ( J ). The mutation associated with the Va phenotype is an alanine to proline substitution at position 419 (A419P) within the predicted fifth transmembrane (TM5) domain of TRPML3. The second Va ( J ) mouse phenotype arose spontaneously from an isoleucine to threonine substitution at position 362 (I362T) that is proximal to the predicted TM3 domain in addition to the existing A419P mutation on TM5. Mice with the Va and Va ( J ) mutations exhibit a spectrum of disease phenotypes from diluted coat color to auditory and vestibular problems, depending on which alleles are present. It has been over 5 years since the discovery of these TRPML3 mutations, and it was just recently that the nature of these mutations has been characterized. In this review, we discuss the molecular and cell physiological effects of the two distinct TRPML3 mutations. We reveal the effects of proline substitution on transmembrane domain structure and channel function and discuss how the Va mutation confers its cytotoxicity, while the Va ( J ) mutation results in an apparent rescue phenotype. Finally, we briefly tackle molecular strategies that have been employed to neutralize the cytotoxic effect and constitutive channel activity of the Va mutation.

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Genetic Analyses of the Mouse Deafness Mutations Varitint-Waddler (Va) and Jerker (Espnje)

Cited by 13 publications

References 28 publications

Life and Death of Sensory Hair Cells Expressing Constitutively Active TRPML3

Life and Death of Sensory Hair Cells Expressing Constitutively Active TRPML3

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

The varitint–waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence

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