• syndromic intellectual disability

This report describes neurodevelopmental disorder with global developmental delay, DOT1L-related, which has been associated with de novo missense mutations. The human gene implicated is DOT1L, which encodes DOT1-like histone lysine methyltransferase, an evolutionarily conserved histone lysine methyltransferase. There is one high-scoring fly ortholog, Dmel\gpp, for which multiple genetic reagents, including loss of function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.

Multiple UAS constructs of Hsap\DOT1L have been introduced into flies, both wild-type and variants associated with human disease. See the 'Disease-Implicated Variants' table below. Hsap\DOT1L variants behave as gain-of-function alleles and lead to increased H3K79 methylation levels. Expression of wild-type Hsap\DOT1L driven in the expression pattern of Dmel\gpp results in a lowered adult eclosion rate; this effect is more pronounced with mutant variants. Surviving adults exhibit wing defects, including wing vein defects and blistering; phenotypes induced by expression of mutant isoforms are more severe than those induced by wild-type Hsap\DOT1L.

Flies homozygous for loss of function alleles of Dmel\gpp exhibit developmental delay and a decrease of H3K79 methylation, and die during larval stages. Ubiquitous RNAi knockdown has similar results.

[updated Jan. 2024 by FlyBase; FBrf0222196]