Mice homozygous for the hypomorphic allele Eya1 bor exhibit cochlear aplasia, with associated deafness, and renal hypoplasia, similar to Branchio-Oto-Renal syndrome (BOR) in humans. Although much is known about the genetics of the disease, little is known about the factors that modify its phenotypic expression. We have recently detailed two modifier loci (Mead1 and Mead2) in a C3HeB/FeJ-Eya1 bor/+ × C57BL/6 J intercross that suppress the ear-related phenotypes in our hypomorphic mutants. In this study we report corroborating evidence for our initial finding with the identification of two modifier loci mapping to the same region in CAST/EiJ and BALB/cJ. Furthermore, we describe an additional locus (Mead3) on chromosome 19 in CAST/EiJ, within which the previously cloned suppressor Nxf1 resides. The suppression effect on cochlear coiling was studied on congenic line(s) for each protective allele. The penetrance and suppressor strength of these alleles vary by strain and locus. Eya1 bor/bor hypomorphs, when homozygous for each of the three protective alleles (CAST/EiJ, C57BL/6 J, or BALB/cJ) at the Mead1 or Mead2 locus, exhibit completely penetrant suppression of cochlear agenesis. At the Mead1 locus, the C57BL/6 J and BALB/cJ alleles have comparable strengths. At the Mead2 locus, the C57BL/6 J and CAST/EiJ alleles have comparable strengths. In contrast, mice with genotype Eya1 bor/bor Mead3CAST/CAST exhibit incomplete penetrance (50%) and a wide range of cochlear coiling (1/4–1½ turns). The identification of these additional modifier alleles could provide crucial clues for evaluating the candidate genes.
Mammalian Genome – Springer Journals
Published: Oct 4, 2008
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