Although the ability of some mouse genetic backgrounds to modify mutant phenotypes is well known, only a handful of the responsible modifier genes have been found. Now Ikeda et al. report a new mouse modifier gene — Mtap1a — that rescues the hearing defects of C56BL/6J (B6) tubby (tub) mutant mice. Importantly, their findings strongly indicate that Mtap1a interacts with proteins that establish and maintain neuronal synapses, and that in the B6 mouse strain, this association is disrupted by Mtap1a alleles that carry polymorphisms in functionally important regions of the gene.

The tub modifier ( moth1 ) locus was mapped to chromosome 2 in 1999, after it was discovered that tub mice retain their hearing on some genetic backgrounds, such as on the AKR/J (AKR), CAST/Ei and 129P2/OlaHsd (129P2) mouse strains, while still developing other tub-associated phenotypes. So, to identify the responsible gene, Ikeda et al. finely mapped the moth1 locus to an interval of 0.17 cM. By screening AKR-derived brain and eye cDNA libraries, Ikeda et al. then identified and mapped four additional genes to this region. One of these was Mtap1a, which encodes the neuron-specific, microtubule-associated protein 1a. On sequencing these cDNAs from the AKR and B6 strains, only Mtap1a contained strain-specific sequence variations — 12 single-nucleotide changes that either altered amino acids or changed the length of an Ala-Pro repeat. The sequencing of CAST/Ei and 129P2 Mtap1a alleles also revealed ten amino-acid-changing polymorphisms between these strains and B6. To prove that Mtap1a is indeed the modifier at moth1, the authors next introduced a 129P2-derived Mtap1a transgene into B6 tub/tub mice, and almost completely rescued their hearing defects.

So, what is the function of Mtap1a and how does it interact with tubby to protect against hearing loss? It appears that, in B6 mice, Mtap1a function is compromised by polymorphisms in a region of the protein that resembles a guanylate kinase (GUK) binding site. GUK domains are present in a membrane-associated family of proteins that are crucial for the establishment of post-synaptic cytoarchitecture. Ikeda et al. found that one member of this family, Psd95, immunoprecipitates with Mtap1a in cerebellar extracts. Moreover, more Psd95 was present in complex with Mtap1a in AKR-derived extracts than in B6 extracts, indicating that sequence polymorphisms in the B6 Mtap1a alleles might affect binding between these two proteins. Future studies should establish the physiological significance of this altered binding in neuronal synaptic function and hearing, and should reveal the still unexplained interaction between Mtap1a and tubby itself.