SYNRG

SYNRG (synergin gamma) is an AP-1 adaptor complex-interacting protein implicated in neuronal function as a coatopathy gene, with homozygous loss-of-function variants (p.Leu1202Pro and p.Gly533*) causing a complex form of hereditary spastic paraplegia (PMID:35090779). In its disease-associated rearranged form, SYNRG is fused to the transcription factor ZNF384 in B-cell acute lymphoblastic leukemia; the resulting SYNRG-ZNF384 fusion protein associates more strongly with the transcriptional coactivator EP300 than wild-type ZNF384 and drives elevated transcription of the differentiation-related genes SALL4 and ID2, with EP300 coexpression specifically potentiating this aberrant activity (PMID:31234226). Beyond its AP-1 association and its role within the ZNF384 fusion, the endogenous molecular function and physiological pathway of SYNRG have not been characterized in the available corpus.

1. 2019 Medium

   Establishing how the SYNRG-ZNF384 leukemic fusion drives transcription clarified that the fusion gains enhanced coactivator engagement rather than acting as a passive bystander.

   Evidence Reporter assays on SALL4/ID2 regulatory regions and GST pull-down of EP300 in a fusion-protein expression system

   PMID:31234226

   Open questions at the time

   • Does not define the function of wild-type full-length SYNRG
   • EP300 interaction shown only in the fusion context, not for native SYNRG
   • No demonstration that elevated SALL4/ID2 transcription is necessary for leukemic transformation in vivo
2. 2022 Low

   Identifying biallelic loss-of-function variants linked SYNRG to a Mendelian neurological disease and positioned it as a coatopathy gene acting through the AP-1 adaptor complex family.

   Evidence Whole-exome sequencing and clinical phenotyping of patients carrying homozygous SYNRG variants

   PMID:35090779

   Open questions at the time

   • No functional validation of the specific variants in vitro or in vivo
   • Direct SYNRG-AP-1 interaction was not experimentally tested in this study
   • Cellular mechanism linking SYNRG loss to spastic paraplegia not established

• The endogenous molecular activity, subcellular localization, and physiological pathway of wild-type SYNRG remain undefined.
• No biochemical definition of SYNRG's role in AP-1-mediated membrane trafficking
• No structural or domain-level mechanism for either disease context
• No connection established between the leukemic fusion biology and the neuronal loss-of-function phenotype