• Alzheimer's disease

Initially identified in an exome-wide association analysis for late-onset Alzheimer disease, the human gene TM2D3 is proposed as a candidate susceptibility locus for Alzheimer disease. A member of the seven transmembrane domain G protein-coupled receptor superfamily, TM2D3 encodes a protein with sequence and structural similarities to the beta-amyloid binding protein, but it does not regulate a response to beta-amyloid peptide. There is a single orthologous gene in Drosophila, amx, for which a classical amorphic mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The wild-type human Hsap\TM2D3 gene has been introduced into flies using constructs with the promoter and regulatory region of the fly amx gene; the human gene with a mutation implicated in late onset Alzheimer cloned into the same context has also been introduced. Variant(s) implicated in human disease tested (as transgenic human gene, TM2D3): the P155L variant form of the human gene has been introduced into flies. Partial heterologous rescue (functional complementation) of the maternal-effect lethal phenotype of Dmel\amx has been demonstrated. The P155L variant form of the human gene fails to rescue.

Mutations in Dmel\amx cause a strong maternal-effect neurogenic phenotype: females homozygous for an amorphic allele of amx are sterile; their offspring exhibit variable neurogenic phenotypes and die in the embryonic stage. A small number of genetic interactions have been described for Dmel\amx; see the amx gene report.

[updated Dec. 2017 by FlyBase; FBrf0222196]