Human genetics

Mutations in Cdh23 , encoding a new type of cadherin, causes stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Di Palma, F. et al. Nature Genet. 27 , 103–107 (2001) [PubMed]

Mutation of CDH23 , encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Bolz, H. et al. Nature Genet. 27 , 108–112 (2001) [PubMed]

Cloned mouse mutant genes often provide new candidates for human genetic disorders, as these studies well exemplify. By positional cloning, Di Palma et al. identified a novel cadherin gene, Cdh23, as a candidate for the deaf waltzer mouse mutant, and found it was mutated in three waltzer alleles. In the neurosensory epithelium, Cdh23 expression is restricted to the inner and outer hair cells, where its loss in waltzer mice causes stereocilia disorganization and hearing impairment. The human orthologue of Cdh23 maps to the region implicated in Usher syndrome type 1D (USH1D), a human disease characterized by hearing and retinal defects. So the group's collaborators, Bolz et al., tested CDH23 as a candidate gene for the disease and found four different CDH23 mutations in USH1D patients. Further studies in waltzer mice promise new insights into the molecular pathology of USH1D.

Immunogenetics

The antibacterial arm of the Drosophila innate immune response requires an IκB kinase. Lu, Y. et al. Genes Dev. 15 , 134–146 (2001) [PubMed]

Both in flies and in mammals, different microbial components activate different signalling pathways of the innate immune response. The Drosophila ird5 gene was identified in a screen for mutants with defective immune responses; in its absence, the anti-fungal response is normal, but flies fail to induce six antibacterial peptide genes in response to infection. The product of the ird5 gene is homologous to the mammalian IκB kinases and is required for the activation of Relish, one of the three known NF-κB family members in flies.

Gene therapy

Glucose-dependent insulin release from genetically engineered K cells. Cheung, A. T. et al. Science 290 , 1959–1962 (2000) [PubMed]

To tackle diabetes using gene therapy, one of the main challenges is to regulate the expression of insulin in response to glucose (see last month's Highlights for another approach to this). Cheung et al. constructed a transgene comprising the human insulin gene and the control region of the glucose-dependent insulinotropic polypeptide (GIP). GIP is expressed in specialized, glucose-responsive gut cells, known as K cells, with kinetics that are very similar to insulin expression. The insulin transgene was expressed in K cells of transgenic mice in a glucose-dependent fashion. Notably, the transgene could also rescue the diabetic phenotype of a chemically induced mouse diabetes model.