• RASopathy

This report describes a Drosophila model of MAP2K1,2-related diseases using the fly gene Dmel\Dsor1. Germline mutations in components of the Ras/Raf/MAPK pathway are associated with a large class of human developmental abnormalities known as RASopathies; these disorders are characterized by a range of structural and functional phenotypes, including cardiac defects and neurocognitive delays. The human MAP2K genes (MAP2K1 and MAP2K2, also known as MEK1 and MEK2) are implicated in a number of RASopathies, including cardiofaciocutaneous syndrome (FBhh0001510). MAP2K1 and MAP2K2 encode dual-specificity protein kinases; there is a single orthologous gene in Drosophila, Dmel\Dsor1. There are multiple genetic reagents available for Dsor1, including amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis.

Neither human gene, MAP2K1 nor MAP2K2, has been introduced into flies.

Animals homozygous for loss-of-functions mutations of Dmel\Dsor1 typically die during embryogenesis. Phenotypes produced by overexpression of wild-type Dsor1 and of mutants analogous to disease-implicated variants have been assessed. Overexpression of wild-type produces no phenotypes detected in the assays used; for the disease-implicated variants, segmentation defects and minor defects of head structures are observed; a variable percentage of animals fail to develop past the embryo state.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): F72S in the fly Dsor1 gene (corresponds to F53S in the human MAP2K1 gene and F57S in the MAP2K2 gene); Y149C in the fly Dsor1 gene (corresponds to Y130C in the human MAP2K1 gene and Y134C in the human MAP2K2 gene); E222K in the fly Dsor1 gene (corresponds to E203K in the human MAP2K1 gene and E207K in the human MAP2K2 gene). See the 'Disease-implicated Variants' table below. Based on the percentage of animals that fail to survive the embryonic stage, the relative severity of the disease-implicated variants has been assessed.

Somatic mutations in MAP2K1 and MAP2K2 are associated with a range of cancers, especially carcinomas. See the Human Disease Model report 'cancer, multiple, MAP2K1,2-related' (FBhh0001022).

[updated Apr. 2023 by FlyBase; FBrf0222196]