Mutation Linked to Genetic Disorder Sheds Light on Heart and Blood Pathologies

Roughly 20 percent of Noonan syndrome cases have now been linked to missense mutations in the SOS1 gene, which encodes a critical component of the RAS/ERK pathway. The findings, reported in the January Nature Genetics, are helping tease apart differences in symptomatology, the range and severity of which can vary greatly among individual patients.

Noonan syndrome—a genetic disease characterized by facial abnormalities, short stature, learning disabilities, and congenital heart malformation—occurs in one out of every 1,000 to 2,500 live births. The condition predisposes its sufferers to leukemia. Previous studies linked 50 percent of syndrome cases to mutations in PTPN11, the gene encoding SHP2, a tyrosine phosphatase required to activate the RAS/ERK cascade. This gain-of-function mutation leads to enhanced activation of ERK, a widely expressed kinase involved in innumerable cellular functions, including mitosis and meiosis.

Although causes of the remaining 50 percent of cases were unknown, evidence suggested that other contributing mutations might also be found in proteins of the MAPK/ERK signaling pathway. Benjamin Neel, the William Bosworth Castle professor of medicine at at Beth Israel Deaconess Medical Center; Amy Roberts, HMS instructor in pediatrics at Children’s Hospital Boston and the HMS–Partners Center for Genetics and Genomics; Raju Kucherlapati, the Paul C. Cabot professor of genetics at HMS and the scientific director of the HMS–Partners center; and colleagues investigated 91 patients with a confirmed diagnosis of Noonan syndrome. Thirteen patients who did not have the known PTPN11 mutation expressed one of nine novel missense mutations in SOS1. None of these autosomal dominant alleles were found in the 188 chromosomes the group examined from non-affected individuals.

SOS1 encodes RAS-GEF, the protein that catalyzes the exchange of GDP with GTP on RAS proteins, enabling them to activate several downstream effectors of the MAPK/ERK pathway. Like the previously identified PTPN11 mutation, Noonan syndrome–associated SOS1 mutations are hypermorphs whose products enhance RAS and ERK activation. The SOS1 mutations, however, provide the first example of activating GEF mutations tied to human disease. The results also implicate SOS1 as a potential human proto-oncogene, given the increased risk of certain leukemias, especially juvenile myelomonocytic leukemia, faced by Noonan syndrome patients. Somatic mutations of PTPN11 have been found in 60 percent of sporadic cases of this childhood disease, and researchers speculate that a similar correlation will be revealed for the newly discovered mutations.

Since uncovering the PTPN11 mutation in 2001, researchers have worked to understand the process by which this genetic defect incites the pathology associated with Noonan syndrome. Although they point out that a larger cohort needs to be analyzed, the authors suggest that the level of ERK hyperactivation may be a key determinant of at least one major symptom. Atrial septal defect—a congenital heart disease that allows blood to travel from the left to the right side of the heart, mixing atrial and venous blood—increased with ERK overexpression and was more common in Noonan syndrome caused by PTPN11 mutations. At the same time, pulmonic stenosis—a condition in which blood flow from the right ventricle to the lungs is obstructed and another common feature of Noonan syndrome—was more frequent in syndrome patients with SOS1 mutations than in those without SOS1 or PTPN11 mutations.

Four Noonan syndrome cases associated with SOS1 mutations were believed to be familial and nine sporadic. Researchers hope this find will aid in prenatal diagnosis and genetic counseling for the disorder.