The effector of the G αq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca 2+ release from the ER, DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca 2+ , both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca 2+ also binds and allosterically activates proteins called calmodulins , which in turn go on to bind and allosterically activate enzymes such as Ca 2+ /calmodulin-dependent kinases (CAMKs).
Through analyses of 530 individuals with diverse phenotypes, Tatton-Brown et al. (2005) identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing the NSD1 gene. Of 166 patients with NSD1 abnormalities for whom photographs were available, Sotos syndrome was clinically diagnosed in 164 (99%) independent of the molecular analysis, indicating that NSD1 aberrations are essentially specific to this condition. Analysis of 124 patients from the United Kingdom suggested that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. Tatton-Brown et al. (2005) reviewed the clinical phenotype of 239 individuals with NSD1 abnormalities and observed that individuals with identical mutations had different phenotypes, that all features present in patients with microdeletions were also observed in patients with mutations, and that there was no correlation between deletion size and clinical phenotype. Tatton-Brown et al. (2005) identified only 13 familial cases and noted that familial cases were more likely than nonfamilial cases to carry missense mutations (p = ), suggesting that the underlying NSD1 mutation mechanism in Sotos syndrome may influence reproductive fitness.