Gaucher disease (GD), caused by biallelic pathogenic variants in GBA1, has evolved from being understood as a macrophage-restricted lysosomal disorder to a multisystem condition involving neuroinflammation, immune dysregulation, and cell-type-specific lipid toxicity. This expanded view has driven a parallel progression in GD mouse model development. Early chemically induced and germline knockout models provided foundational insights but were limited by perinatal lethality or incomplete phenotypic fidelity. Subsequent generations of conditional, inducible, and lineage-specific models enabled dissection of visceral and neuronopathic manifestations and clarified the contributions of macrophages, B cells, neurons, microglia, osteoblasts, and endothelial cells to disease pathogenesis. More recent humanized immune and gene-edited platforms, together with multi-omics integration, now allow modeling of genotype-specific biology and therapeutic response with greater translational precision. In this review, we synthesize the evolution of GD mouse models across these eras, evaluate their strengths and limitations, and highlight species-specific challenges including differences in lipid metabolism, immune architecture, and the absence of the GBAP1 pseudogene in mice that influence interpretation and clinical translation. We outline emerging strategies for incorporating patient-derived mutations, modifier pathways, and clinically meaningful endpoints into future models. Our aim is to provide a coherent framework that bridges murine and human GD biology and supports the development of more predictive platforms to accelerate mechanistic discovery, biomarker development, and therapeutic innovation across all subtypes of GD.

Background/Objectives: Gaucher disease (GD) is characterized by significant phenotypic heterogeneity, even among patients with identical GBA1 genotypes, suggesting the role of genetic and/or epigenetic modifiers. The enzymatic defect and pathological accumulation of glucosylceramide (GlcCer) lead to chronic metabolic inflammation, potentially interacting with other biological pathways to influence disease expression. Methods: This study leveraged one of the world’s most deeply phenotyped cohorts of GD patients, drawn from a major tertiary referral center, with prolonged longitudinal follow-up. Whole exome sequencing (WES) was conducted on 275 extensively characterized patients, focusing on those exhibiting complex phenotypes. Results: Eighteen patients (6.5%) presented with atypical manifestations not fully explained by GD. WES revealed additional genetic diagnoses, including hereditary hemochromatosis (n=5), Familial Mediterranean Fever (n=4), homozygous MSH6 mutation-associated hereditary cancer predisposition (n=2), and others. These concurrent genetic diseases can modify GD presentation and complicate clinical management. Conclusions: This work underscores the importance of recognizing complex phenotypes in GD, identifying modifier genes, and informing precision medicine strategies for improved patient outcomes.

Spermidine N -acetyltransferase (SpeG) acetylates and thus neutralizes toxic polyamines. Studies indicate that SpeG plays an important role in virulence and pathogenicity of many bacteria, which have evolved SpeG-dependent strategies to control polyamine concentrations and survive in their hosts. In Escherichia coli , the two-component response regulator RcsB is reported to be subject to Nε-acetylation on several lysine residues, resulting in reduced DNA binding affinity and reduced transcription of the small RNA rprA ; however, the physiological acetylation mechanism responsible for this behavior has not been fully determined. Here, we performed an acetyltransferase screen and found that SpeG inhibits rprA promoter activity in an acetylation-independent manner. Surface plasmon resonance analysis revealed that SpeG can physically interact with the DNA-binding carboxyl domain of RcsB. We hypothesize that SpeG interacts with the DNA-binding domain of RcsB and that this interaction might be responsible for SpeG-dependent inhibition of RcsB-dependent rprA transcription. This work provides a model for SpeG as a modulator of E. coli transcription through its ability to interact with the transcription factor RcsB. This is the first study to provide evidence that an enzyme involved in polyamine metabolism can influence the function of the global regulator RcsB, which integrates information concerning envelope stresses and central metabolic status to regulate diverse behaviors.