Cappuccio, G. | bioRxiv Science

bioRxiv2025

MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation

Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders. Metabolic control is fundamental to cellular function, influencing energy production, signaling, epigenetic regulation, and tissue homeostasis1. Nowhere is this more critical than in the brain, where tightly regulated metabolic networks sustain high energetic demands and support neuronal development, synaptic plasticity, and circuit formation2. Disruptions in these networks are increasingly implicated across a spectrum of neurodevelopmental disorders3-5, yet their precise metabolic signatures and mechanistic contributions remain poorly understood.

neuroscience↗

bioRxiv2019

Variants in the degron of AFF3 cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

The ALF transcription factor paralogs, AFF1, AFF2, AFF3 and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role of AFF3 variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe KIdney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for Seizures, H for Hypertrichosis, I for Intellectual disability and P for Pulmonary involvement), partially overlapping the AFF4 associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif of AFF3 exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.\n\nWhereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.\n\nTranscriptome analyses as well as the partial phenotypic overlap of syndromes associated with AFF3 and AFF4 variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested

genetics↗