International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

11:15 - 11:30 HRS

DEAFNESS AND PIGMENTATION DEFECTS IN VARITINT-WADDLER (Va) MICE CAUSED BY MUTATIONS IN Mcoln3, A NEW MEMBER OF THE MUCOLIPIN GENE FAMILY

K. Noben-Trauth
National Institute on Deafness and Other Communication Disorders

Co-Authors: Di Palma F, Belyantseva I, Kim H, Kachar B
Institutions: National Institute on Deafness and Other Communication Disorders

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 semi-dominant mouse mutant, varitint-waddler (Va), exhibits early-onset hearing loss, vestibular defects, pigmentation abnormalities and perinatal lethality.  A second allele, VaJ, arose in a cross segregating for Va.  Coat color variegation, hearing loss and hair cell defects are less severe in VaJ.  We observe the first signs of inner and outer hair cell defects at embryonic day 17.5, as evident by the disorganized hair bundle.  Using a positional cloning strategy, we identify two new members of the mucolipin gene familiy (Mcoln2 and Mcoln3) in the 350kb VaJ minimal interval and provide evidence that Mcoln3 is the gene mutated in varitint-waddler.  Mcoln3 encodes a putative six-transmembrane protein with sequence and motif similarities to the family of non-selective transient-receptor-potential (TRP) ion channels.  In the Va allele an Ala419Pro substitution occurs in the fifth transmembrane domain of Mcoln3 and in VaJ a second sequence alteration (Ile362Thr) occurring in cis partially rescues the Va allele.  By immunostaining, we localize Mcoln3 to vesicular compartments of hair cells and plasmamembrane of stereocilia.  Our data suggest that Mcoln3 acts as a non-selective ion channel and is involved in intracellular and/or vesicular ion homeostasis.  Hence, we identify a new 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.


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