A knockout of the Nesp55 transcript has been generated in mice through introduction, by homologous recombination in ES cells, of a small deletion at the translation initiation site [60]. This mutation leads to a complete ablation of Nesp55 protein after maternal transmission, without affecting the expression of other Gnas transcripts. Nesp55 knockout mice appear to have no overt phenotypic abnormalities and are fertile. However, behavioral studies of these mice using several distinct tasks have revealed increased reactivity to novel environments, but these mice do not differ from wild-type mice in general locomotion and anxiety. Although the role of this protein at the molecular level remains to be explored, the findings in the Nesp55 deficient mice appear to be consistent with the localization of this protein in specific parts of the central nervous system, particularly noradrenergic locus coeruleus [61]. In humans, loss of NESP55 expression occurs as a result of a gain of methylation at its promoter (observed in some patients with pseudohypoparathyroidism type-Ib). This defect, however, does not appear to lead to an obvious phenotype, because no significant differences have been identified between patients with the gain of NESP55 methylation and those without this epigenetic alteration [62, 63].
