In humans mutations in KDM A KDM
In humans, mutations in KDM5A, KDM5B, and KDM5C are found in patients with ID, implicating KDM5-regulated transcription in the development or activity of neuronal tissues (Vallianatos and Iwase, 2015). KDM5D is Y-linked, and its role in cognition remains uncharacterized. Mutations in KDM5C are the most well studied and are predicted to account for 0.7%–3% of males with X-linked ID (XLID) (Gonçalves et al., 2014, Ropers and Hamel, 2005). To date, 31 mutations in KDM5C have been observed segregating in families with non-syndromic or syndromic ID (Gonçalves et al., 2014, Grafodatskaya et al., 2013, Vallianatos and Iwase, 2015). One mutation in KDM5A has been identified in a family study of autosomal recessive non-syndromic ID (Najmabadi et al., 2011). Notably, this missense mutation affects an arginine that is also found altered in KDM5C in XLID patients, providing additional support for a causal link between this mutation and cognitive defects (Tzschach et al., 2006). Genome-wide correlative studies have also identified nine missense, nonsense, and frameshift mutations in KDM5B in autism patients who display ID (De Rubeis et al., 2014, Iossifov et al., 2014). While nonsense and frameshift mutations are expected to result in a loss of KDM5 proteins, missense mutations are more likely to alter the transcription of a clinically relevant subset of target genes. Emphasizing the importance of residues affected by missense alleles, all disease-associated mutations in KDM5A, KDM5B, and KDM5C characterized to date occur in Ketorolac tromethamine salt mg that are evolutionarily conserved between humans and Drosophila. Current models propose that disrupting the enzymatic activity of KDM5 proteins leads to cognitive impairment in human patients (Vallianatos and Iwase, 2015). Consistent with this, eight of nine missense mutations in KDM5C examined show significantly reduced in vitro histone demethylase activity (Brookes et al., 2015, Iwase et al., 2007, Rujirabanjerd et al., 2010, Tahiliani et al., 2007). However, these effects were modest (≤2-fold), and no mutant proteins have been examined for demethylase activity defects in an in vivo context. This point is particularly salient in light of the fact that missense mutations in KDM5 proteins do not cluster in the catalytic JmjC domain and are instead spread throughout the protein (Vallianatos and Iwase, 2015). Whether the enzymatic activity of KDM5 proteins is a critical contributor to neuronal function therefore remains unknown. Direct genotype-phenotype investigations in human patients have been confounded by the variability in clinical presentation of patients with a mutation in KDM5C. Mutations predicted to be genetic null alleles cause mild to severe ID and can be non-syndromic or syndromic with other features such as short stature, seizures, and aggression (Gonçalves et al., 2014, Tzschach et al., 2006). Diverse genetic backgrounds may contribute to this variability. In addition, clinical severity may be influenced by the efficiency of compensation by other KDM5 family proteins since KDM5B expression was upregulated in lymphoblastoid cells from a patient with a frameshift KDM5C mutation (Jensen et al., 2010). The molecular links between KDM5 family proteins and neuronal (dys)function remain unclear, underscoring the need for a genetically amenable model. A major step forward in this goal came from the generation of a KDM5C knockout mouse strain designed to model the effects of nonsense and other mutations expected to result in a complete loss of KDM5C gene function (Iwase et al., 2016, Scandaglia et al., 2017). KDM5C knockout mice had defective learning, aberrant social interactions, hyperreflexia, and propensity for seizures. Despite recapitulating many of the clinical features of patients with mutations in KDM5C, genome-wide transcriptome analyses of frontal cortex and amygdala neurons in KDM5C knockout mice did not reveal any clear pathways linked to ID (Iwase et al., 2016). An additional animal model could therefore provide insight into the genes and pathways that are dysregulated by ID-associated mutations in KDM5 family proteins.