{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Diacylglycerol kinase κ (DGKK) is a lipid‐modifying enzyme that phosphorylates diacylglycerol into phosphatidic acid, thereby regulating key signaling pathways that influence both neural function and urogenital development. In the context of male genital formation, multiple independent studies have identified that genetic variants in DGKK are strongly associated with an increased risk of hypospadias, particularly in cases exhibiting mild to moderate phenotypes. Expression analyses in developing mouse external genitalia indicate that DGKK is localized to differentiating squamous epithelial cells of the urethral plate and groove, suggesting that it may serve as a marker or mediator of squamous cell differentiation during urethral development (1,2,3,4,5,6). Moreover, large-scale genotyping and meta-analyses in different populations support the conclusion that DGKK variants contribute to hypospadias susceptibility, although their influence appears to diminish in more severe cases (7,8,9,14)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the nervous system, DGKK plays a critical role in modulating lipid signaling that impacts synaptic protein translation and membrane properties. In fragile X syndrome models, the Fragile X Mental Retardation Protein (FMRP) has been shown to bind predominantly to the mRNA encoding DGKK. Loss of FMRP leads to diminished DGKK expression and activity, which in turn contributes to dendritic spine abnormalities, altered synaptic plasticity, and behavioral deficits; conversely, restoring DGKK levels ameliorates these defects. In addition, regulatory small nucleolar RNAs have been implicated in controlling DGKK expression, thereby linking its function to broader neurodevelopmental disorders (10,11)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n More broadly, DGKK is one among several diacylglycerol kinase isoforms that display tissue- and cell type-specific expression. While some studies note that DGKK expression may be limited or undetectable in certain tissues such as skeletal muscle, its presence in reproductive organs – including expression in spermatocytes of the testis – underscores a potential role in sexual development and gametogenesis (12,13). Collectively, these findings emphasize that DGKK functions as a master regulator of both lipid signaling in neuronal contexts and cellular differentiation processes during male external genital development."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "b", "children": [{"type": "t", "text": "Citations:"}]}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Loes F M van der Zanden, Iris A L M van Rooij, Wout F J Feitz, et al. 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