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Mutanlallemand  ( mtl ) and  Belly Spot and Deafness  ( bsd ) are two new spontaneous alleles of the  Lmx1a  gene in mice. Homozygous mutants show head tossing and circling behaviour, indicative of vestibular defects, and they have short tails and white belly patches of variable size. The analysis of auditory brainstem responses (ABR) showed that  mtl  and  bsd  homozygotes are deaf, whereas heterozygous and wildtype littermates have normal hearing. Paint-filled inner ears at E16.5 revealed that  mtl  and  bsd  homozygotes lack endolymphatic ducts and semicircular canals and have short cochlear ducts. These new alleles show similarities with  dreher  ( Lmx1a ) mutants. Complementation tests between  mtl  and  dreher  and between  mtl  and  bsd  suggest that  mtl  and  bsd  are new mutant alleles of the  Lmx1a  gene. To determine the  Lmx1a  mutation in  mtl  and  bsd  mutant mice we performed PCR followed by sequencing of genomic DNA and cDNA. The  mtl  mutation is a single point mutation in the 3′ splice site of exon 4 leading to an exon extension and the activation of a cryptic splice site 44 base pairs downstream, whereas the  bsd  mutation is a genomic deletion that includes exon 3. Both mutations lead to a truncated LMX1A protein affecting the homeodomain ( mtl ) or LIM2-domain ( bsd ), which is critical for LMX1A protein function. Moreover, the levels of  Lmx1a  transcript in  mtl  and  bsd  mutants are significantly down-regulated.  Hmx2/3  and  Pax2  expression are also down-regulated in  mtl  and  bsd  mutants, suggesting a role of  Lmx1a  upstream of these transcription factors in early inner ear morphogenesis. We have found that these mutants develop sensory patches although they are misshapen. The characterization of these two new  Lmx1a  alleles highlights the critical role of this gene in the development of the cochlea and vestibular system.

Mutanlallemand (mtl) and Belly Spot and Deafness (bsd) Are Two New Mutations of Lmx1a Causing Severe Cochlear and Vestibular Defects