Chapter 4 - Induced pluripotent stem cells for modeling Noonan, Noonan Syndrome with Multiple Lentigines, and Costello Syndromes

Abstract

Germline mutations in genes that reside along the canonical RAS-mitogen-activated protein kinase (MAPK) signaling pathway lead to disorders known as RASopathies, rare autosomal dominant diseases that include Noonan syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSMLs), and Costello Syndrome (CS). Clinical presentation of these disorders is similar, systemically affecting multiple tissues and organs including the heart and brain, yet distinct. However, while differential activation of RAS-MAPK and RAS-PI3K-AKT signaling has been attributed to the cause of NS, NSML, and CS, the nuances for how each of these pathways elicits distinct disease characteristics remains unclear. To begin to address these concerns and to elucidate the mechanisms of these disorders, animal model systems have been generated and utilized. However, these nonhuman model systems do not always effectively translate to human disease function and/or therapeutic efficacy in patients. To circumvent these issues, inducible pluripotent stem cells (iPSCs) along with clustered regularly interspaced short palindromic repeats associated protein 9 genome editing technology has recently been developed to study disease mechanisms associated with RASopathies. Here, we will discuss the current iPSC-related research as it pertains to NS, NSML, and CS, with particular focus on how this technology has advanced our understanding of RASopathies and the cardiac and neurodevelopmental defects associated with mutations in patients.