The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear

• Published in: Human molecular genetics Vol. 9; no. 1; pp. 79 - 85
• Main Authors: PHIPPARD, D, BOYD, Y, REED, V, FISHER, G, MASSON, W. K, EVANS, E. P, SAUNDERS, J. C, CRENSHAW, E. B
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 2000; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; brn4 gene; Chromosome Mapping; DNA-Binding Proteins; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Ear, Inner - embryology; Ear, Inner - physiology; Female; Gene Expression Regulation, Developmental; Gene Rearrangement; Immunohistochemistry; Male; Medical sciences; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Mutant Strains; Mutation; Nerve Tissue Proteins; Non tumoral diseases; Otorhinolaryngology. Stomatology; POU Domain Factors; pou3f4 gene; Reflex, Acoustic - physiology; Reflex, Startle - genetics; Regulatory Sequences, Nucleic Acid; Sex Factors; slf gene; Transcription Factors - genetics; Transcription Factors - metabolism; X Chromosome; Genetic mapping; Sex linked character; Embryonic development; Animal model; Linkage; Rodentia; Auditory disorder; Gene expression; Inner ear; Hearing loss; Vertebrata; Mammalia; Mouse; ENT disease; X-Chromosome; Mutation; Transcription factor
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.1.79

We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4.