The RASopathies are a group of developmental syndromes caused by

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

s in genes belonging to the

Ras/MAPK pathway The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling m ...

. Common features include

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital h ...

s, skin abnormalities, and craniofacial abnormalities.

MAPK pathway

The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway. This well-established MAPK pathway in cell biology governs several crucial cellular. It encompasses the RAS/RAF/MEK/ERK signaling cascade. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK pathway and the transcription factor extracellular signal-related kinase (ERK), which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation, differentiation, migration, survival, apoptosis and cell death. With this cascade, various isoforms of RAS, RAF, MEK, and ERK exhibit differences in efficacy, function, and, notably, carcinogenic potential. Defects in this signaling cascade are associated with diseases. The pathophysiology of NF1, Noonan, Watson and Legius syndromes fit into the RASopathy model. The RASopathies are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Costello Syndrome and Cardiofaciocutaneous syndrome are also included in RASopathy. Common features include intellectual disability, congenital heart defects, skin abnormalities, craniofacial abnormalities and tendency for tumor formation.

List of RASopathies

Known RASopathies include the following: * Capillary malformation-AV malformation syndrome (CV-AVM) * Cardiofaciocutaneous syndrome (CFC) *

Neurofibromatosis type I Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...

(NF1) * Watson syndrome * Noonan syndrome (NS) * Costello syndrome (CS) * Legius syndrome, also known as NF1-like syndrome * Noonan syndrome with multiple lentigines (NSML), formerly called LEOPARD syndrome * SYNGAP1-related intellectual disability

Somatic mutation A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline muta ...

s in the Ras/MAPK pathway can cause cancers and disorders such as RAS-associated autoimmune leukoproliferative disorder (RALD) or

juvenile myelomonocytic leukemia Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia (cancer of the blood) that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic mye ...

(JMML). These syndromes may share some features with RASopathies but are not considered true RASopathies if caused by somatic mutation. Generally, RASopathies increase the risk of developing cancers. Neurodevelopmental or psychiatric disorders such as

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

autism spectrum Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

disorder, and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

occur at higher rates in individuals with RASopathies.

Genetics

RASopathies are caused by germline mutations which result in overall activation of the Ras/MAPK pathway. Mutations in the following genes are associated with one or more types of RASopathy: *

HRAS GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 (human), chromosome 11 at position 15.5, ...

KRAS ''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the ce ...

* NRAS * RRAS * RIT1 * NF1 * RASA1 * RASA2 * SYNGAP1 *

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with Ras protein, Ras proteins to phosphorylate GDP into GTP, or from an inacti ...

* SOS2 * CBL *

PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...

* BRAF * RAF1 *

MAP2K1 Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the ''MAP2K1'' gene. Function The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mit ...

* MAP2K2 * MAP3K8 *

SPRED1 Sprouty-related, EVH1 domain-containing protein 1 (pronounced ''spread-1'') is a protein that in humans is encoded by the ''SPRED1'' gene located on chromosome 15q13.2 and has seven coding exons. Function SPRED-1 is a member of the Sprouty fa ...

SPRY1 Protein sprouty homolog 1 is a protein that in humans is encoded by the ''SPRY1'' gene. See also *Neurofibromin 1 Neurofibromin (NF-1) is a protein that is encoded in humans, in the ''NF1'' gene. ''NF1'' is located on chromosome 17. Neur ...

* MYST4 * LZTR1 * A2ML1

References

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