Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice

Jennifer M. Hilton, Morag A. Lewis, M'hamed Grati, Neil Ingham, Selina Pearson, Roman A. Laskowski, David J. Adams, Karen P. Steel

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Inflammation of the middle ear (otitis media) is very common and can lead to serious complications if not resolved. Genetic studies suggest an inherited component, but few of the genes that contribute to this condition are known. Mouse mutants have contributed significantly to the identification of genes predisposing to otitis media. Results: The dearisch mouse mutant is an ENU-induced mutant detected by its impaired Preyer reflex (ear flick in response to sound). Auditory brainstem responses revealed raised thresholds from as early as three weeks old. Pedigree analysis suggested a dominant but partially penetrant mode of inheritance. The middle ear of dearisch mutants shows a thickened mucosa and cellular effusion suggesting chronic otitis media with effusion with superimposed acute infection. The inner ear, including the sensory hair cells, appears normal. Due to the low penetrance of the phenotype, normal backcross mapping of the mutation was not possible. Exome sequencing was therefore employed to identify a non-conservative tyrosine to cysteine (Y71C) missense mutation in the Islet1 gene, Isl1 Drsh. Isl1 is expressed in the normal middle ear mucosa. The findings suggest the Isl1 Drshmutation is likely to predispose carriers to otitis media.Conclusions: Dearisch, Isl1 Drsh, represents the first point mutation in the mouse Isl1 gene and suggests a previously unrecognized role for this gene. It is also the first recorded exome sequencing of the C3HeB/FeJ background relevant to many ENU-induced mutants. Most importantly, the power of exome resequencing to identify ENU-induced mutations without a mapped gene locus is illustrated.

Original languageEnglish (US)
Article numberR90
JournalGenome Biology
Volume12
Issue number9
DOIs
StatePublished - Sep 21 2011
Externally publishedYes

Fingerprint

Exome
otitis media
penetrance
missense mutation
Penetrance
Otitis Media
Missense Mutation
mutation
ears
gene
mice
mutants
Genes
Middle Ear
genes
Mucous Membrane
mucosa
Gene Components
Otitis Media with Effusion
Mutation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

Hilton, J. M., Lewis, M. A., Grati, M., Ingham, N., Pearson, S., Laskowski, R. A., ... Steel, K. P. (2011). Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice. Genome Biology, 12(9), [R90]. https://doi.org/10.1186/gb-2011-12-9-r90

Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice. / Hilton, Jennifer M.; Lewis, Morag A.; Grati, M'hamed; Ingham, Neil; Pearson, Selina; Laskowski, Roman A.; Adams, David J.; Steel, Karen P.

In: Genome Biology, Vol. 12, No. 9, R90, 21.09.2011.

Research output: Contribution to journalArticle

Hilton, JM, Lewis, MA, Grati, M, Ingham, N, Pearson, S, Laskowski, RA, Adams, DJ & Steel, KP 2011, 'Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice', Genome Biology, vol. 12, no. 9, R90. https://doi.org/10.1186/gb-2011-12-9-r90
Hilton, Jennifer M. ; Lewis, Morag A. ; Grati, M'hamed ; Ingham, Neil ; Pearson, Selina ; Laskowski, Roman A. ; Adams, David J. ; Steel, Karen P. / Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice. In: Genome Biology. 2011 ; Vol. 12, No. 9.
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