• syndrome

SREBF2-related syndrome with dermatologic, neurologic, and skeletal defects is a newly described autosomal dominant disease. The SREBF2 gene encodes a transcription factor that regulates genes related to cholesterol biosynthesis. There is a single orthologous gene in Drosophila, Dmel\SREBP, that is also orthologous to a second gene in human, SREBF1. Multiple genetic reagents have been generated for Dmel\SREBP, including loss-of-function mutations, RNAi-targeting constructs, and overexpression constructs.

Multiple UAS constructs of the human Hsap\SREBF2 gene have been introduced into flies, including wild-type and variants implicated in this disease. Two de novo variants ( SREBF2:p.Arg519His or SREBF2:p.Arg519Gly ) have been characterized in Drosophila; see the 'Disease-Implicated Variants' table below.

Using a pan-neuronal driver, overexpression in flies of either of the characterized disease-implicated human variants induces age-dependent neurological deficits, as assayed in climbing assays, bang-sensitivity assays, and electroretinograms of the eye to measure neuronal response to light flashes.

Overexpression in neurons of either fly SREBP or wild-type human Hsap\SREBF2 induces glial lipid droplet formation; however, overexpression of either Hsap\SREBF2 variant fails to do so. When nonvariant and variant Hsap\SREBF2 transcripts are coexpressed, significantly disrupted glial lipid droplet accumulation is observed. This latter result supports a dominant-negative mechanism for the two characterized variants.

[updated Jan. 2025 by FlyBase; FBrf0222196]