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Mutations in Mcoln3 Associated with Deafness and Pigmentation Defects in Varitint-Waddler (Va) Mice

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Mutations in Mcoln3 Associated with Deafness and Pigmentation Defects in Varitint-Waddler (Va) Mice Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice Federica Di Palma*, Inna A. Belyantseva†, Hung J. Kim*‡, Thomas F. Vogt§¶, Bechara Kachar†, and Konrad Noben-Trauth*ʈ *Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850; †Section on Structural Cell Biology, Laboratory of Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 50 Convent Drive, Bethesda, MD 20892; and §Department of Molecular Biology, Princeton University, Princeton, NJ 08544 Edited by Jeremy Nathans, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 3, 2002 (received for review July 18, 2002) Deafness in spontaneously occurring mouse mutants is often stria vascularis, resulting in the loss of the endochochlea poten- associated with defects in cochlea sensory hair cells, opening an tial, and deafness (7, 8). avenue to systematically identify genes critical for hair cell struc- To identify genes important for hair cell function, we adopted ture and function. The classical semidominant mouse mutant a positional cloning approach of mouse mutations with known varitint-waddler (Va) exhibits early-onset hearing loss, vestibular defects in the OC. Two mutations, Va and VaJ, arose spontane- defects, pigmentation abnormalities, and perinatal lethality. A ously at the varitint-waddler locus, causing a distinct allele- second allele, VaJ, which arose in a cross segregating for Va, shows specific set of phenotypes (9–11). Most severely affected are a less severe phenotype. By using a positional cloning strategy, we Va͞Va mice, which exhibit deafness, circling behavior, sterility, identify two additional members of the mucolipin gene family an almost entirely white coat color, and reduced viability (9). The (Mcoln2 and Mcoln3) in the 350-kb VaJ minimal interval and mildest phenotype is seen in ϩ͞VaJ mice, which are viable, show provide evidence for Mcoln3 as the gene mutated in varitint- normal vestibular function, display only limited variegation and waddler. Mcoln3 encodes a putative six-transmembrane-domain coat color dilution, and have some residual hearing (10, 12, 13). J͞ J ϩ͞ protein with sequence and motif similarities to the family of Va Va and Va mice show intermediate and similar pheno- nonselective transient-receptor-potential (TRP) ion channels. In the types. Hearing tests and anatomical studies associated hearing J Va allele an Ala419Pro substitution occurs in the fifth transmem- loss in Va mice with a primary defect in the sensory epithelium brane domain of Mcoln3, and in VaJ, a second sequence alteration and reduced pigmentation in melanocytes located in the stria (Ile362Thr) occurring in cis partially rescues the Va allele. Mcoln3 vascularis (12). These defects were found to occur indepen- localizes to cytoplasmic compartments of hair cells and plasma dently, suggesting that Va acts as a cell-autonomous factor. Thus, mi W membrane of stereocilia. Hair cell defects are apparent by embry- unlike other spotted deaf mouse mutants (Mitf , Kit , and Sl onic day 17.5, assigning Mcoln3 an essential role during early hair Kitl ), in which neuroepithelial degeneration develops second- cell maturation. Our data suggest that Mcoln3 is involved in ion ary to the stria vascularis defects, Va might reveal an interesting homeostasis and acts cell-autonomously. Hence, we identify a cellular and molecular principle shared by inner ear hair cells and molecular link between hair cell physiology and melanocyte func- melanocytes. tion. Last, MCOLN2 and MCOLN3 are candidate genes for heredi- Materials and Methods tary and͞or sporadic forms of neurosensory disorders in humans. Mice and DNA. Mutant and common inbred mouse strains were obtained from The Jackson Laboratory. B6Fe-a͞a-Hoxa13Hd erception and transmission of acoustic stimuli in the mam- VaJ mice were backcrossed to the C57BL͞6J strain for10 gen- Pmalian cochlea is a stratified process involving the establish- erations and outcrossed to C3HeB͞FeJ, and the resulting prog- ment of the endolymph through melanocytes located in the stria eny were intercrossed. RSV͞Le-Va͞ϩ mice were outcrossed to vascularis; deflection of stereocilia situated on the apical surface C3HeB͞FeJ and then intercrossed. Intercrossed offspring from of sensory hair cells in the organ of Corti (OC); opening of Va and VaJ strains were used for phalloidin staining and immu- mechanosensitive transduction channels, nonselectively perme- nocytochemistry. Genomic DNA was obtained from The Jack- ϩ able for cations, including Ca2 ; and transmission of the elec- son Laboratory. Animal care and procedures were in accordance trical impulse onto the eighth cranial nerve for further process- with National Institutes of Health guidelines (Animal Study ing in the auditory brainstem and cortex. Mutations affecting Protocol 821͞97). these processes are often associated with circling behavior, ataxic movements, and pigmentation anomalies. Circling and Physical Map. The physical map was constructed by screening the waltzing phenotypes are usually caused by mutations primarily ES-129͞SvJ I (Incyte Genomics, Palo Alto, CA) and the affecting structure and function of hair cells, which, directly or C57BL͞6J RPCI-23 (Roswell Park Cancer Institute) mouse indirectly, lead to stereocilia disorganization and hair cell de- generation. Genes critical for hair cells encode a functionally heterogenous group of proteins that include structural proteins This paper was submitted directly (Track II) to the PNAS office. (myosins, cadherins, and spectrins), extracellular matrix proteins Abbreviations: TRP, transient receptor potential; BAC, bacterial artificial chromosome; IHCs, inner hair cells; OHCs, outer hair cells; OC, organ of Corti; Pn, postnatal day n;En, (tectorins), transmembrane proteins (channels, pumps, ion embryonic day n. pores, and exchangers), and others (for review see ref. 1). Among Data deposition: The sequences reported in this paper have been deposited in the GenBank the many coat color and spotting mutants, dominant spotting database (accession nos. AC068974, AC079941, AY083531, AY083532, and AY083533). W St mi (Kit ), steel (Kitl ), microphthalmia (Mitf ), and varitint- See commentary on page 14613. waddler (Va), exhibit deafness in combination with pigmentation ‡Present address: Department of Otolaryngology and Head and Neck Surgery, Georgetown defects. The genes underlying W, St, and mi have been shown to University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007-2197. encode the c-Kit receptor tyrosine kinase (2, 3), its ligand Kitl ¶Present address: Department of Molecular Pharmacology, Merck Research Laboratories, (4, 5), and the Mitf transcription factor (6), respectively. Muta- Merck & Co., 770 Sumneytown Pike Road, West Point, PA 19486. tions in Kit and Mitf impair the survival of melanocytes in the ʈTo whom correspondence should be addressed. E-mail: [email protected]. 14994–14999 ͉ PNAS ͉ November 12, 2002 ͉ vol. 99 ͉ no. 23 www.pnas.org͞cgi͞doi͞10.1073͞pnas.222425399 Downloaded by guest on October 1, 2021 bacterial artificial chromosome (BAC) libraries. We screened min. After three 10-min washes in PBS, samples were mounted the ES-129͞SvJ I BAC library by PCR with the flanking by using the ProLong Antifade kit (Molecular Probes) and recombinant markers (D3Mit85, D3Mit260, D3Mit259, and examined with a laser scanning confocal microscope (LSM 510, D3Mit292). Probes from the BAC ends of the ES-129͞SvJ I BAC Zeiss). clones were used to screen the RPCI-23 library by hybridization. BAC clones were sized by restriction endonuclease digestion Immunocytochemistry. To obtain antibodies against Mcoln3 with NotI (NEB) followed by pulsed-field gel electrophoresis (GenBank accession no. AY083531), rabbits were immunized (PFGE) on a Chef-DRII apparatus (Bio-Rad). We sequenced (Covance Research Products, Denver, PA) against synthetic BAC ends with vector-specific primers by using BigDye termi- peptide 1, NH2-446-RVSECLFSLINGDDMFS-COOH, and nator chemistry (Applied Biosystems) and an ABI 377 sequencer peptide 2, NH2-529-KDLPNSGKYRLEDDPPGSLL-COOH (Applied Biosystems). To confirm the chromosomal location of (Princeton Biomolecules, Langhorne, PA). Immunocytochem- each identified clone and to establish the orientation of Sp6 and istry was performed as described (14). OCs were dissected as T7 ends, we developed sequence-tagged sites (STSs), primer described above. After permeabilization in 0.5% Triton X-100 sets, and probes from the end sequences of BAC clones and for 30 min, samples were washed three times in PBS for 10 min mapped them to the predicted VaJ physical interval by using PCR and incubated in 5% normal goat serum (Life Technologies, cross-screening experiments and Southern blot hybridizations. Grand Island, NY) and 2% BSA (ICN) in PBS for2htoblock Overlaps among individual BAC clones were confirmed by nonspecific binding sites. After incubation with primary anti- fingerprinting with HindIII and͞or EcoRI single or double bodies at 3–6 ␮g͞ml in blocking solution for2hatroom digestions. temperature, samples were washed several times in PBS and incubated in a 1:200 dilution of the fluorescein-conjugated Gene Identification and Mutation Analysis. Draft sequences from anti-rabbit IgG secondary antibody (Amersham Pharmacia Bio- RP23-108E10 and RP23-121J1 BAC clones were
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