Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Abstract

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

“…WES data processing, including sequence alignment to GRCh37/GRCh38, and variant filtering and prioritization by allele frequency, predicted functional impact, and inheritance were performed as pre-viously reported. 42,[47][48][49][50][51][52][53][54][55][56][57][58] Variants' validation and segregation analyses were carried out by Sanger sequencing.…”

In vivo Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale

“…Lastly, WES sequencing in a group of patients showing neurodevelopmental alterations within the RASopathy spectrum coupled to functional validation in nematodes has more recently established the pathogenicity of de novo mutations affecting MAPK1 (ERK2) directly and possibly their ability to interact with regulators and effectors (Motta et al, 2020). The underlying mechanism and plausible perturbance of fine signaling balances within developmental programs remain to be characterized.…”

“…Of note, we previously identified a different class of mutations affecting the same genes as the cause of a clinically variable neurodevelopmental disorder (Martinelli et al, 2018), emphasizing the requirement of functional characterization analyses to casually associate genomic variants with disease and decipher the underlying mechanisms. More recently, we identified activating mutations in the gene encoding the key effector of the MAPK signaling cascade, MAPK1 [OMIM: 176948], as cause of a neurodevelopmental disease within the RASopathies spectrum (Motta et al, 2020). Again, in vivo assays in the context of cell differentiation and morphogenesis contributed to the validation of the pathogenicity of the mutations during embryonic development.…”

Manic and Depressive Symptoms in Children Diagnosed with Noonan Syndrome

“…In a significant proportion of patients with NS, loss-of-function (recessive form) or dominant negative (dominant form) mutations in LZTR1 have been reported. NS is clinically related to other developmental disorders collectively denominated “RASopathies”, sharing the upregulation of the Ras–MAPK signaling cascade as a mechanism of disease [ 10 , 11 , 12 ]. Among these, Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome), Mazzanti syndrome (MS), neurofibromatosis type 1, and Legius syndrome have been characterized [ 13 ].…”

“…Among these, Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome), Mazzanti syndrome (MS), neurofibromatosis type 1, and Legius syndrome have been characterized [ 13 ]. New conditions are also emerging [ 10 ]. In RASopathies, a cognitive deficit significantly varies depending on the gene involved and the type of mutation.…”