Longo, N. | Search bioRxiv

bioRxiv2026

ARID5B mutations cause a neurodevelopmental syndrome with neuroinflammation episodes

Genetic disorders affecting the epigenetic machinery constitute a major group of neurodevelopmental conditions. Pathogenic variants in several ARID transcription factors--particularly ARID1A, ARID1B, and ARID2--cause Coffin-Siris syndromes, all characterized by intellectual disability (ID). These genes encode core subunits of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex. In contrast, ARID family members that function in other regulatory complexes have remained largely unexplored in neurodevelopmental disease. Here, we identify 29 individuals carrying heterozygous ARID5B variants, of which 24 (83%) introduce premature termination codons in the exceptionally long final exon, one affects the exon 9 splice donor site, and four are missense variants in conserved domains within the N-terminal half of the protein. Using a CRISPR-Cas9 knock-in mouse model harboring the p.Q522Ter variant, together with in vitro assays, we investigated the functional consequences of C-terminal ARID5B truncations. All affected individuals presented with global developmental delay or ID--most commonly mild--and frequent speech and language impairment. Recurrent features included kidney malformations, behavioral difficulties, and recurrent infections of the respiratory and urinary tracts. Two individuals experienced central nervous system inflammation, and two infants presented with persistent pulmonary hypertension. Remarkably, 19 of 29 variants (66%) cluster within the first quarter of exon 10, are de novo, and escape nonsense-mediated mRNA decay (NMD), which we confirmed for two variants affecting seven individuals. Variants outside this region were inherited. Heterozygous mice exhibited developmental and behavioral abnormalities, while homozygous mutations was perinatally lethal. Truncations and a small deletion within a predicted nuclear localization signal (NLS) caused cytosolic mislocalization of ARID5B, whereas the isolated C-terminal half retained nuclear localization, suggesting an independent distal NLS. Collectively, these findings define ARID5B-related neurodevelopmental disorder as a distinct clinical entity and reveal how disruption of specific ARID5B domains impacts protein localization, mammalian development, immune and neurobehavioral function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/698931v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@158e8d9org.highwire.dtl.DTLVardef@1f014dorg.highwire.dtl.DTLVardef@18e6e7forg.highwire.dtl.DTLVardef@1f886e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2017

Global analysis of plasma lipids identifies liver-derived acyl-carnitines as a fuel source for brown fat thermogenesis

Cold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified plasma acylcarnitines as the most significantly changed lipid class in response to the cold. Here we show that acylcarnitines provide fuel for brown fat thermogenesis. In response to the cold, FFAs released from adipocytes activate the nuclear receptor HNF4 to stimulate the expression of genes involved in acylcarnitine metabolism in the liver. Conditional deletion of HNF4 in hepatocytes blocks the cold-induced changes in hepatic gene expression, lowering circulating long chain acylcarnitine (LCAC) levels, and impairing their ability to adapt to the cold. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlights an elegant mechanism whereby white adipose tissue provides FFAs for hepatic carnitilation to generate plasma LCAC as a fuel source for BAT thermogenesis.\n\nHighlightsO_LIBlood acylcarnitine levels increase in response to the cold.\nC_LIO_LIFFA mobilization in response to the cold activates hepatic HNF4 and stimulates genes involved in acylcarnitine metabolism.\nC_LIO_LIBrown adipocytes metabolize palmitoylcarnitine.\nC_LIO_LICarnitine administration improves thermogenic response in aged mice.\nC_LI\n\nETOCSimcox et al identified acylcarnitines as a novel source of energy for thermogenesis. In response to the cold, the liver activates a transcriptional program through the transcription factor HNF4, leading to increased acylcarnitine levels. They also find that aging mice have reduced acylcarnitine levels and an impaired thermogenic response in the cold. Increasing acylcarnitine levels in old mice increases their ability to adapt to the cold. Their studies discover a physiological role for acylcarnitines in thermogenesis.\n\nGraphical AbstractCold exposure stimulates the sympathetic nervous system to release noradrenaline (NA). Activation of {beta}3-adrenergic receptors stimulates FFA release and activation of the transcription factor HNF4 in the liver. This leads to increased gene expression of enzymes involved in acylcarnitine metabolism. The acylcarnitines are released in the blood to provide fuel for brown fat thermogenesis. These studies highlight the role of the liver in the thermogenic response.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC=\"FIGDIR/small/132241_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (80K):\norg.highwire.dtl.DTLVardef@1282891org.highwire.dtl.DTLVardef@17f7c7forg.highwire.dtl.DTLVardef@c6b637org.highwire.dtl.DTLVardef@1e4f40d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗