Drosophila NSD deletion induces developmental anomalies similar to those seen in Sotos syndrome 1 patients

Background Haploinsufficiency of the human nuclear receptor binding suppressor of variegation 3–9, enhancer of zeste, and trithorax ( SET ) domain 1 (NSD1 ) gene causes a developmental disorder called Sotos syndrome 1 (SOTOS1), which is associated with overgrowth and macrocephaly. NSD family proteins encoding histone H3 lysine 36 (H3K36) methyltransferases are conserved in many species, and Drosophila has a single NSD homolog gene, NSD . Objective To gain insight into the biological functions of NSD1 deficiency in the developmental anomalies seen in SOTOS1 patients using an NSD -deleted Drosophila mutant. Methods We deleted Drosophila NSD using CRISPR/Cas9-mediated targeted gene knock-out, and analyzed pleiotropic phenotypes of the homozygous mutant of NSD ( NSD −/− ) at various developmental stages to understand the roles of NSD in Drosophila . Results The site-specific NSD deletion was confirmed in the mutant. The H3K36 di-methylation levels were dramatically decreased in the NSD −/− fly. Compared with the control, the NSD −/− fly displayed an increase in the body size of larvae, similar to the childhood overgrowth phenotype of SOTOS1 patients. Although the NSD mutant flies survived to adulthood, their fecundity was dramatically decreased. Furthermore, the NSD −/− fly showed neurological dysfunctions, such as lower memory performance and motor defects, and a diminished extracellular signal-regulated kinase (ERK) activity. Conclusions The NSD -deleted Drosophila phenotype resembles many of the phenotypes of SOTOS1 patients, such as learning disability, deregulated ERK signaling, and overgrowth; thus, this mutant fly is a relevant model organism to study various SOTOS1 phenotypes.