title: Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1.
abstract: Otoconia are biominerals within the utricle and saccule of the inner ear that are critical for the perception of gravity and linear acceleration. The classical mouse mutant tilted (tlt) and a new allele, mergulhador (mlh), are recessive mutations that affect balance by impairing otoconial morphogenesis without causing collateral deafness. The mechanisms governing otoconial biosynthesis are not known. Here we show that tlt and mlh are mutant alleles of a novel gene (Otopetrin 1, Otop1), encoding a multi-transmembrane domain protein that is expressed in the macula of the developing otocyst. Both mutants carry single point mutations leading to non-conservative amino acid substitutions that affect two putative transmembrane (TM) domains (tlt, Ala(151)-->Glu in TM3; mlh, Leu(408)-->Gln in TM8). Otop1 and Otop1-like paralogues, Otop2 and Otop3, define a new gene family with homology to the C. elegans and D. melanoganster DUF270 genes.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University Medical School, 660 South Euclid Ave, St Louis, MO 63110, USA.
authors.forename: Belen
authors.initials: B
authors.lastname: Hurle
authors.forename: Elena
authors.initials: E
authors.lastname: Ignatova
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Massironi
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Xavier
authors.initials: X
authors.lastname: Rios
authors.forename: Isolde
authors.initials: I
authors.lastname: Thalmann
authors.forename: Ruediger
authors.initials: R
authors.lastname: Thalmann
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D002462:Cell Membrane / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004331:Drosophila melanogaster; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism*; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D015837:Vestibular Diseases / Q000235:genetics* / Q000473:pathology*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D008565:Membrane Proteins; D012333:RNA, Messenger; C479478:otopetrin 1 protein, mouse