A novel 11 base pair deletion in KMT2C resulting in Kleefstra syndrome 2.

BACKGROUND: Haploinsufficiency of the Lysine Methyltransferase 2C (KMT2C) gene results in the autosomal dominant disorder, Kleefstra syndrome 2. It is an extremely rare neurodevelopmental condition, with 14 previous reports describing varied clinical manifestations including dysmorphic features, delayed psychomotor development and delayed growth. METHODS: Here, we describe a female with global developmental delay, attention deficit disorder, dyspraxia, short stature and subtle non-specific dysmorphic features. To identify causative mutations, whole exome sequencing was performed on the proband and her younger brother with discrete clinical presentation. RESULTS: Whole exome sequencing identified a novel de novo heterozygous 11 bp deletion in KMT2C (c.1759_1769del), resulting in a frameshift mutation and early termination of the protein (p.Gln587SerfsTer7). This variant is the second-most N-terminal reported mutation, located 4171 amino acids upstream of the critical enzymatically active SET domain (required for chromatin modification and histone methylation). CONCLUSION: The majority of the other reported mutations are frameshift mutations upstream of the SET domain and are predicted to result in protein truncation. It is thought that truncation of the SET domain, results functionally in an inability to modify chromatin through histone methylation. This report expands the clinical and genetic characterisation of Kleefstra syndrome 2.

Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. EXPERIMENTAL APPROACH: This study investigated the neuroprotective effects of the small-molecule STING inhibitor n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines Tnf-α, Il-1ß and Cxcl10 compared to their vehicle-treated counterparts 2 h post-TBI. CONCLUSION AND IMPLICATIONS: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma-induced inflammation and neuroprotective potential.